Rarefaction In Patients Research Articles

Independent Prognostic and Predictive Role of Interstitial Macrophages in Kidney Biopsies of IgA Nephropathy Patients.

A relevant percentage of IgAN patients experience a progressive decline in kidney function. According to the KDIGO guidelines, proteinuria and eGFR are the only validated prognostic markers. The role of interstitial macrophages in kidney biopsies of IgAN patients and the outcome of patients treated with renin-angiotensin system inhibitors (RASBs) alone or combined with glucocorticoids were evaluated. Clinical and laboratory records (age, gender, hypertension, hematuria, proteinuria, eGFR, serum creatinine, and therapy), MEST-C parameters of the Oxford classification, C4d deposition, peritubular capillaries, and glomerular and interstitial macrophages in 47 IgAN patients undergoing kidney biopsy consecutively between 2003 and 2016 were examined. A high number of interstitial macrophages significantly correlated with peritubular capillary rarefaction and impairment of kidney function. Cox's multivariable regression analysis revealed that a value > 19.5 macrophages/HPF behaved as an independent marker of an unfavorable outcome. Patients exhibiting > 19.5 macrophages/HPF treated at the time of diagnosis with RASBs combined with methylprednisolone had an estimated probability of a favorable outcome higher than patients treated with RASBs alone. Thus, a value > 19.5 macrophages/HPF in IgAN biopsies can predict an unfavorable outcome and endorse a well-timed administration of glucocorticoids. Studies evaluating urine biomarkers associated with peritubular capillary rarefaction in patients with marked macrophage infiltration may help personalized treatment decisions.

Microvascular rarefaction in patients with cerebrovascular events.

Capillary density rarefaction and endothelial dysfunction contribute to chronic hypoperfusion and cerebral small vessel disease. Previous animal experiments revealed spatiotemporal microvascular remodeling directing post-stroke brain reorganization. We hypothesized that microcirculatory changes during acute cerebrovascular events could be reflected systemically and visualized sublingually. In a prospective observational trial in vivo sublingual sidestream darkfield videomicroscopy was performed in twenty-one patients with either acute stroke (n=13 ischemic, n=1 ischemic with hemorrhagic transformation and n=2 hemorrhagic stroke) or transitory ischemic attacks (n=5) within 24h after hospital admission and compared to an age- and sex-matched control group. Repetitive measurements were performed on the third day and after one week. Functional and perfused total capillary density was rarefied in the overall patient group (3060 vs 3717μm/mm2, p=0.001 and 5263 vs 6550μm/mm2, p=0.002, respectively) and in patients with ischemic strokes (2897 vs. 3717μm/mm2, p<0.001 and 5263 vs. 6550μm/mm2, p=0.006, respectively) when compared to healthy controls. The perfused boundary region (PBR), which was measured as an inverse indicator of glycocalyx thickness, was markedly related to red blood cell (RBC) filling percentage (regarded as an estimate of microvessel perfusion) in the overall patient group (r=-0.843, p<0.001), in patients with ischemic strokes (r=-0.82, p=0.001) as well as in healthy volunteers (r=-0.845, p<0.001). In addition, there were significant associations between platelet count or platelet aggregation values (as measured by whole blood impedance aggregometry) and microvascular parameters in the overall patient collective, as well as in patients with ischemic strokes. In conclusion, cerebrovascular events are associated with altered systemic microvascular perfusion.

Mitochondrial dysfunction-mediated decline in angiogenic capacity of endothelial progenitor cells is associated with capillary rarefaction in patients with hypertension via downregulation of CXCR4/JAK2/SIRT5 signaling.

BackgroundHypertensive patients exhibit decline in capillary density and endothelial progenitor cells (EPCs). However, whether capillary rarefaction in hypertension is associated with defect angiogenesis of EPCs remains unknown. We hypothesized that impaired mitochondrial function of late EPCs in hypertension is associated with the structural lack of capillary microcirculation via deficient CXCR4/JAK2/SIRT5 signaling.MethodsWe performed capillary microcirculation detection in hypertensive patients and healthy subjects. Angiogenic capacity and mitochondrial function of circulating EPCs were evaluated. The underlying mechanisms were further investigated by genetic inhibition and overexpression.FindingsCapillary density of nail fold and eye fundus were significantly reduced in hypertensive patients, which was paralleled to decreased in vitro late EPC function and in vivo angiogenic capacity. Meanwhile the decline of EPC function in hypertension was accompanied by impaired mitochondrial ultrastructure, diminished mitochondrial membrane potential, reduced oxygen consumption, increased ROS generation and NADH level. Rotenone induced inhibition of oxygen consumption rate, excessive ROS generation and loss of MMP, which markedly decreased the in vitro functions of EPCs. Furthermore, SIRT5 expression of EPCs in hypertension was markedly reduced, which was correlated to mitochondrial dysfunction. CXCR4 gene transfer enhanced SIRT5 expression, improved mitochondrial functions and augmented angiogenic capacity of EPCs. The beneficial impacts of SIRT5 up-regulation on late EPC-mediated angiogenesis can be abrogated by blockade of CXCR4/JAK2/SIRT5 signaling pathway.InterpretationMitochondrial dysfunction-mediated fall in angiogenic capacity due to deficient CXCR4/JAK2/SIRT5 signaling of late EPCs is probably responsible for the capillary rarefaction in hypertension. Our findings provide insight into the potential of EPC mitochondria as a novel target for the treatment of hypertension-related loss of microvascular density.FundsNational Nature Science Foundation of China, 973Program, the Nature Science Foundation of Guangdong.

GW29-e0918 Effect of Exercise on Improving Microvascular Rarefaction in Patients with Hypertension: Primary Results of EXCAVATION-CHN1

GW29-e0918 Effect of Exercise on Improving Microvascular Rarefaction in Patients with Hypertension: Primary Results of EXCAVATION-CHN1

Mitochondrial Dysfunction-Mediated Decline in Angiogenic Capacity of Circulating Endothelial Progenitor Cells is Associated with Capillary Rarefaction in Patients with Hypertension

Hypertensive patients exhibit decline in capillary density and endothelial progenitor cells (EPCs). However, whether capillary rarefaction in hypertension is associated with defect angiogenesis of EPCs remains unknown. We hypothesized that impaired mitochondrial function of late EPCs in hypertension is associated with the structural lack of capillary microcirculation via deficient CXCR4/JAK2/SIRT5 signaling. Capillary density of nail fold was significantly reduced in hypertensive patients, which was paralleled to decreased in vitro late EPC function and in vivo angiogenic capacity. Meanwhile the decline of EPC function in hypertension was accompanied by impaired mitochondrial ultrastructure, diminished mitochondrial membrane potential, reduced oxygen consumption, increased ROS generation and NADH level. Furthermore, SIRT5 expression of EPCs in hypertension was markedly reduced, which was correlated to mitochondrial dysfunction. CXCR4 gene transfer enhanced SIRT5 expression, improved mitochondrial functions and augmented angiogenic capacity of EPCs. The beneficial impacts of SIRT5 up-regulation on late EPC-mediated angiogenesis can be abrogated by blockade of CXCR4/JAK2/SIRT5 signaling pathway. Mitochondrial dysfunction-mediated fall in angiogenic capacity due to deficient CXCR4/JAK2/SIRT5 signaling of late EPCs is probably responsible for the capillary rarefaction in hypertension. Our findings provide insight into the potential of EPC mitochondria as a novel target for the treatment of hypertension-related loss of microvascular density. Funding: This work was supported by the National Nature Science Foundation (31530023, 81500205, 81671379) of China, 973 Program (2013CB531200), the Nature Science Foundation (2016A030310184, 2016A020215056) of Guangdong and Science and Technology Planning Project (2017A020215085) of Guangdong. Declaration of Interest: None. Ethical Approval: The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China).

Retinal capillary rarefaction in patients with untreated mild-moderate hypertension

BackgroundMicrovascular rarefaction influences peripheral vascular resistance, perfusion and metabolism by affecting blood pressure and flow pattern. In hypertension microvascular rarefaction has been described in experimental animal studies as well as in capillaroscopy of skin and biopsies of muscle tissue in patients. Retinal circulation mirrors cerebral microcirculation and allows non-invasive investigations. We compared capillary rarefaction of retinal vessels in hypertensive versus normotensive subjects.MethodsIn this study retinal capillary rarefaction in 70 patients with long time (more than 67 month of disease duration) and 64 patients with short time hypertension stage 1 or 2 has been compared to 55 healthy control subjects, who participated in clinical trials in our Clinical Research Center (www.clinicaltrials.gov: NCT01318395, NCT00627952, NCT00152698, NCT01319344). Retinal vascular parameters have been measured non-invasively and in vivo in perfusion image by scanning laser Doppler flowmetry (Heidelberg Engineering, Germany). Capillary rarefaction was assessed by capillary area (CapA) (in pixel-number) and intercapillary distance (ICD) (in μm). Additionally retinal capillary flow (RCF) was measured.ResultsICD was greater in the long time hypertensive group compared to healthy individuals (24.2 ± 6.3 μm vs 20.1 ± 4.2 μm, p = 0.001) and compared to short time hypertensive patients (22.2 ± 5.2 μm, p = 0.020). Long time hypertensive patients showed less CapA compared to healthy people (1462 ± 690 vs 1821 ± 652, p = 0.005). Accordingly, RCF was significantly lower in the long time hypertensive group compared to the healthy control group (282 ± 70 AU vs 314 ± 60 AU, p = 0.032). Our data indicate a lower level of retinal capillary density in hypertensive patients, especially in those with long time hypertension.ConclusionPatients with hypertension stage 1 or 2 showed retinal capillary rarefaction in comparison to healthy normotensive subjects. Retinal capillary rarefaction was intensified with duration of disease.

Retinal Capillary Rarefaction in Patients with Type 2 Diabetes Mellitus.

PurposeIn diabetes mellitus type 2, capillary rarefaction plays a pivotal role in the pathogenesis of end-organ damage. We investigated retinal capillary density in patients with early disease.MethodsThis cross-sectional study compares retinal capillary rarefaction determined by intercapillary distance (ICD) and capillary area (CapA), measured non-invasively and in vivo by scanning laser Doppler flowmetry, in 73 patients with type 2 diabetes, 55 healthy controls and 134 individuals with hypertension stage 1 or 2.ResultsIn diabetic patients, ICD was greater (23.2±5.5 vs 20.2±4.2, p = 0.013) and CapA smaller (1592±595 vs 1821±652, p = 0.019) than in healthy controls after adjustment for differences in cardiovascular risk factors between the groups. Compared to hypertensive patients, diabetic individuals showed no difference in ICD (23.1±5.8, p = 0.781) and CapA (1556±649, p = 0.768).ConclusionIn the early stage of diabetes type 2, patients showed capillary rarefaction compared to healthy individuals.

Excretion of anti-angiogenic proteins in patients with chronic allograft dysfunction

We have recently documented the appearance of an anti-angiogenic peptide, endorepellin, in the urine of patients with chronic allograft dysfunction (CAD). Here, we analyzed using enzyme-linked immunosorbent assay the excretion of anti-angiogenic peptides endostatin, pigment epithelium-derived factor (PEDF) and Kruppel-like factor-2 (KLF-2), in healthy individuals, patients with stable graft function and patients with various degrees of CAD. In healthy subjects and patients with CAD-0, endostatin, PEDF and KLF-2 excretions were at the level of detection. In contrast, there were significant differences between the patients with CAD-3 and CAD-0, CAD-1 and healthy controls for endostatin and CAD-0 versus CAD-3 for PEDF, but no differences in KLF-2 excretion. Receiver operating characteristic (ROC) curve analyses demonstrated a highly discriminative profile for all three biomarkers: the combination of these parameters offered 83% sensitivity and 90% specificity in distinguishing CAD-0 from CAD-1-3. The quality of these potential biomarkers of CAD was, however, highest in discriminating CAD status in biopsy-proven cases and dropped when CAD-0 was diagnosed based on clinical criteria. In conclusion, these findings indicate the diagnostic potential of urinary detection of endostatin, PEDF and to lesser degree KLF-2 and suggest a mechanistic role played by anti-angiogenic substances in the developing vasculopathy and vascular rarefaction in patients with CAD.

A New Semi-quantitative Approach for Analysing 3T Diffusion Tensor Imaging of Optic Fibres and Its Clinical Evaluation in Glaucoma

Diffusion tensor imaging can depict rarefaction of the optical fibers. Manual segmentation is time consuming. The purposes of the study were (1) to present a new semiquantitative segmentation approach for analyzing 3-T diffusion tensor imaging of optical fibers and (2) to clinically test the new approach by comparing optic fiber rarefaction in patients with glaucoma to that in age-matched, healthy controls. To perform semiautomated and quantitative segmentation of the optical radiation, a Mathcad-based software program was developed. The results were compared to the manual evaluation of the images performed by two experienced neuroradiologists. The eyes of 42 subjects (22 patients with glaucoma and 20 controls) aged 37 to 86 years were assessed in full ophthalmologic examinations. Magnetic resonance imaging was performed using a 3-T high-field scanner. The evaluation using the new approach matched 94% with manually acquired rarefaction of the optical radiation; Cronbach's α was >0.81 for calculation of the manually and semiautomatically derived volumes. The new approach seems to be robust and is clearly faster compared to the more tedious manual segmentation. Using diffusion tensor imaging at 3 T, it could be shown that there was increasing atrophy of the optical radiation (fourth neuron) with increasing age in patients with glaucoma. Compared to age-matched, healthy patients, more pronounced atrophy of the fourth neuron was found in patients with glaucoma.

Mechanism of bevacizumab-induced arterial hypertension: Relation with skin capillary rarefaction in patients treated for metastatic colorectal cancer

3557 Background: Bevacizumab in combination with chemotherapy is the standard treatment of metastatic colorectal cancer (mCRC). Hypertension (HT) has been reported in all studies, in particular grade 3 HT (3 - 16%) (Saif and Mehra, 2006 Expert Opinion on Drug Safety). The mechanism underlying bevacizumab-related HT is not yet clearly understood and recent studies have demonstrated that humoral factors involving the renin-angiotensin system and the sympathetic nervous system had little role in the observed increase in BP. As far as microvascular rarefaction has been reported in all forms of human and experimental HT, we tested the hypothesis that anti VEGF therapy could induce microvascular rarefaction in non tumoral tissues and, thus, result in an increase in BP Methods: For 16 patients treated for mCRC, Bevacizumab was administered at 5 or 7.5 mg/kg every 2 or 3 weeks depending on the frequency of concomitant chemotherapies which were FOLFIRI (4 patients) or XELOX (12 patients) We used intravital video-microscopy to measure basal and maximal (during venous congestion) skin capillary densities in the dorsum of the fingers. Aortic stiffness was evaluated using pulse wave velocity, and microvascular endothelial function was assessed by laser-Doppler flowmetry combined with iontophoresis of three different doses of acetylcholine (ACh). All measurements were performed in 16 patients (mean age: 59±10 y) before and after a 6 month treatment with bevacizumab (mean cumulative dose: 3.16±0.90 g) Results: are summarized in the following table : Conclusions: Pharmacological blockage of VEGF receptors result in endothelial dysfunction and capillary rarefaction in humans. Both changes are closely associated with and seem responsible for the rise in blood pressure observed in patients receiving this treatment. This could be considered for future study about anti- angiogenic treatment and HT. [Table: see text] No significant financial relationships to disclose.

Microvascular Plasticity and Experimental Heart Failure

Angiogenesis is an essential process in adulthood during wound healing and restoration of blood flow to injured tissues. Angiogenesis is regulated by a very sensitive interplay of growth factors and inhibitors; their imbalance can lead to very diverse diseases. Excessive angiogenesis is involved in malignant, diabetic retinopathy and inflammatory disorders (eg, rheumatoid arthritis, psoriasis, atherosclerosis). Conversely, insufficient angiogenesis may underlie conditions such as ischemic heart diseases, stroke, hypertension, and diabetes. Hence, during the evolution of these degenerative pathologies, inadequate blood vessel growth and insufficient microvascular density leads to poor circulation and tissue suffering or, ultimately, necrosis and death.1 In several physiological conditions, such as muscular exercise training and detraining, acclimatization to altitude, and aging, an adaptation of the microvascular network structure and function to new conditions has been reported.2,3 Interestingly, there is a close link between cerebral angiogenesis and learning; during cognitive decline in relation to senescence or degenerative cerebral diseases, microvascular density is decreased in specific cerebral areas. Specifically, there is a striking relationship between the capillary density, the cerebral tissue blood flow, the local glucose use, and other measures of neuronal signaling, such as the NA+/K+ ATPase (reviewed in Reference 4). Therefore, microvascular plasticity, defined as the ability of the arteriole and capillary network to adapt to the metabolic local conditions by proangiogenesis or antiangiogenesis processes, likely plays a key role in many tissue homeostatic processes. In hypertension, the role of microcirculation (arteriolar and capillary) is of particular importance in increasing periph-eral resistance …

Rarefaction of skin capillaries in patients with anginal chest pain and normal coronary arteriograms.

Patients with arterial hypertension often have a reduction in capillary density (rarefaction) and a reduction in coronary flow reserve because of functional and structural alterations of the coronary microcirculation. Patients with chest pain and normal coronary arteriograms may have coronary microvascular dysfunction, but it is not known whether capillary rarefaction plays a role in the pathogenesis of this syndrome. The aim of this study was to compare capillary density in hypertensive and normotensive subjects with anginal chest pain and normal coronary arteriograms vs asymptomatic hypertensives and healthy controls. We studied 49 patients with typical anginal chest pain, positive exercise testing and normal coronary arteriograms; 22 were hypertensive and 27 were normotensive. We used intra-vital video-microscopy to examine the skin of the dorsum of the middle finger of the non-dominant hand before and after maximization of perfused capillaries with venous congestion. Mean capillary density was significantly lower in patients with chest pain and normal coronary arteriograms independent of their blood pressure level, compared to normotensive healthy controls. Differences were found both at baseline [51+/-2 (hypertensive) and 52+/-2 (normotensive) vs 65+/-2 (controls) per 0.56 mm(2) respectively], (P<0.0001) and after maximization [57+/-3 (hypertensive) and 59+/-2 (normotensive) versus 75+/-3 (controls) respectively] (P<0.0001). Skin capillary density is significantly lower in patients with chest pain and normal coronary arteriograms compared to normotensive controls. The pathophysiological importance of capillary rarefaction in patients with chest pain and normal coronary arteriograms remains unknown. Further studies are needed to determine whether the abnormality is associated with myocardial flow disturbances such that the findings can be extended to the heart.

American Heart Association Prevention Conference. IV. Prevention and Rehabilitation of Stroke. Etiology of stroke.

The diagnosis of arterial stroke differentiates ischemia from hemorrhage. The former may be due to arterial occlusion or stenosis, the latter to leakage or rupture of an artery. Computed tomography (CT) and magnetic resonance imaging (MRI) have shown that this basic differentiation cannot be reliably made from the history and clinical examination alone. Of the clinical stroke syndromes, only Wallenberg’s syndrome has not been reported to be due to hemorrhage. When CT or MRI is not available for diagnosis, spinal tap is reliably positive only when the aneurysm or arteriovenous malformation has ruptured into the subarachnoid space; the results are often normal when a small hemorrhage occurs in the parenchyma. For some therapies, notably neuroprotective agents, the potential benefits for ischemia do not seem to be offset by potential harm in the case of hemorrhage. However, because fibrinolytics, antithrombotic agents, or surgery are treatment options, diagnostic certainty is essential to avoid harming the patient. Most—but not all—strokes have a sudden or rapidly evolving onset. Differential diagnosis of sudden change in focal neurological status includes seizures or postepileptic paralysis, hemorrhage into a tumor (itself a form of stroke), and migraine. Neuroimaging helps to differentiate between these and the cause of short-lived symptoms (transient ischemic attack [TIA]) usually presumed due to ischemia but possibly due to new-onset infarction or hemorrhage. More precise classification of stroke into a pathogenic subtype (embolism, thrombosis, decreased perfusion or “lacunar” infarction, leakage, or rupture) evades the best clinical skills. The classification of stroke mechanism depends on the presence of risk factors for stroke (preexisting condition or circumstance epidemiologically related to stroke) and etiologies (disease directly causing the mechanism) that implicate the cause of stroke in a given patient. However, more than one risk factor and etiology are frequently present in the same patient and may be related …