Angiopathic Changes Research Articles

Retinal arterial blood flow and retinal changes in patients with sepsis: preliminary study using fluorescein angiography

BackgroundAlthough tissue perfusion is often decreased in patients with sepsis, the relationship between macrohemodynamics and microcirculatory blood flow is poorly understood. We hypothesized that alterations in retinal blood flow visualized by angiography may be related to macrohemodynamics, inflammatory mediators, and retinal microcirculatory changes.MethodsRetinal fluorescein angiography was performed twice during the first 5 days in the intensive care unit to observe retinal abnormalities in patients with sepsis. Retinal changes were documented by hyperfluorescence angiography; retinal blood flow was measured as retinal arterial filling time (RAFT); and intraocular pressure was determined. In the analyses, we used the RAFT measured from the eye with worse microvascular retinal changes. Blood samples for inflammation and cerebral biomarkers were collected, and macrohemodynamics were monitored. RAFT was categorized as prolonged if it was more than 8.3 seconds.ResultsOf 31 patients, 29 (93%) were in septic shock, 30 (97%) required mechanical ventilation, 22 (71%) developed delirium, and 16 (51.6%) had retinal angiopathies, 75% of which were bilateral. Patients with prolonged RAFT had a lower cardiac index before (2.1 L/kg/m2 vs. 3.1 L/kg/m2, P = 0.042) and during angiography (2.1 L/kg/m2 vs. 2.6 L/kg/m2, P = 0.039). They more frequently had retinal changes (81% vs. 20%, P = 0.001) and higher intraocular pressure (18 mmHg vs. 14 mmHg, P = 0.031). Patients with prolonged RAFT had lower C-reactive protein (139 mg/L vs. 254 mg/L, P = 0.011) and interleukin-6 (39 pg/ml vs. 101 pg/ml, P < 0.001) than those with shorter RAFT.ConclusionsRetinal angiopathic changes were more frequent and cardiac index was lower in patients with prolonged RAFT, whereas patients with shorter filling times had higher levels of inflammatory markers.

Kaolin-induced chronic hydrocephalus accelerates amyloid deposition and vascular disease in transgenic rats expressing high levels of human APP.

BackgroundNormal pressure hydrocephalus (NPH) is most common in the elderly and has a high co-morbidity with Alzheimer’s disease (AD) and cerebrovascular disease (CVD). To understand the relationship between NPH, AD and CVD, we investigated how chronic hydrocephalus impacts brain amyloid-beta peptide (Aβ) accumulation and vascular pathology in an AD transgenic rodent model. Previously we showed that the altered CSF physiology produced by kaolin-hydrocephalus in older wild-type Sprague–Dawley rats increased Aβ and hyperphosphorylated Tau (Silverberg et. al. Brain Res. 2010, 1317:286–296). We postulated that hydrocephalus would similarly affect an AD rat model.MethodsThirty-five transgenic rats (tgAPP21) that express high levels of human APP and naturally overproduce Aβ40 were used. Six- (n = 7) and twelve-month-old (n = 9) rats had hydrocephalus induced by cisternal kaolin injection. We analyzed Aβ burden (Aβ40, Aβ42 and oligomeric Aβ) and vascular integrity (Masson trichrome and Verhoeff-Van Gieson) by immunohistochemistry and chemical staining at 10 weeks (n = 8) and 6 months (n = 5) post hydrocephalus induction. We also analyzed whether the vascular pathology seen in tgAPP21 rats, which develop amyloid angiopathy, was accelerated by hydrocephalus. Age-matched naïve and sham-operated tgAPP21 rats served as controls (n = 19).ResultsIn hydrocephalic tgAPP21 rats, compared to naïve and sham-operated controls, there was increased Aβ 40 and oligomeric Aβ in hippocampal and cortical neurons at 10 weeks and 6 months post-hydrocephalus induction. No dense-core amyloid plaques were seen, but diffuse Aβ immunoreactivity was evident in neurons. Vascular pathology was accelerated by the induction of hydrocephalus compared to controls. In the six-month-old rats, subtle degenerative changes were noted in vessel walls at 10 weeks post-kaolin, whereas at six months post-kaolin and in the 12-month-old hydrocephalic rats more pronounced amyloid angiopathic changes were seen, with frequent large areas of infarction noted.ConclusionsKaolin-hydrocephalus can accelerate intraneuronal Aβ40 accumulation and vascular pathology in tgAPP21 rats. In addition, disrupted CSF production and reduced CSF turnover results in impaired Aβ clearance and accelerated vascular pathology in chronic hydrocephalus. The high co-morbidity seen in NPH, AD and CVD is likely not to be an age-related coincidence, but rather a convergence of pathologies related to diminished CSF clearance.

Severity of leukoaraiosis, leptomeningeal collaterals, and clinical outcomes after intra-arterial therapy in patients with acute ischemic stroke

Background and purposeLeukoaraiosis (LA) is defined as ischemic white matter lesions associated with increased stroke risk and poor post-stroke outcomes. These lesions are likely the result of diffuse angiopathic changes...

White matter angiopathy is common in pediatric patients with intractable focal epilepsies

The blood-brain barrier (BBB) and functional organization of blood vessels is severely affected in many epilepsy disorders. This was repetitively shown with respect to the cause, effect and treatment of seizures. In the present study, we investigated pathomorphological abnormalities of blood vessels in a cohort of young patients with chronic intractable seizures submitted to an epilepsy surgery program. Histopathological examination was performed in surgical specimens obtained from 87 children with intractable epilepsies. Immunohistochemistry was employed to further characterize the basal membrane as well as specific cellular and tissue reactions. Pathological findings were correlated with clinical data including antiepileptic drug prescription. We identified an intriguing pattern of white matter angiopathy in 64.4% of our patient cohort. Major alterations included splitting of the basal membrane into endothelial and parenchymal leaves, which was restricted to arterioles and capillaries of the white matter and resulted in an extensively enlarged perivascular space. These cavities contained numerous blood cells and showed a spongiform appearance at the ultrastructural level. Angiopathic changes occurred independent from specific epilepsy-associated lesions, i.e., dysplasia, neoplasia, or hippocampal sclerosis, and showed no correlation with antiepileptic drug treatment or seizure semiologies. A high frequency of spongiform white matter angiopathy was identified in young patients with chronic epilepsies. The severity of basal membrane pathology and adjacent tissue reaction is compatible with compromised BBB function. Further clinicopathological investigations will be mandatory to clarify its relation to the cause or consequence of seizures in children with intractable seizures.

Hyperbaric oxygen therapy of angiopathic changes in patients with inherited gene imbalance

Phenotype match inherited by genes is in most cases present in monozygotic twins. Their phenotypic resemblance is unfortunately characterized by strong susceptibility for the development of chronic non-infectious diseases. One of the most common non-infectious chronic diseases that are phenotipically represented in twins is diabetes mellitus. Genetic imbalance is, in most cases, placed in 2, 3, 7, 8, 11, 12, 19 and 20 chromosomal pair of the human genome. This study describes a pair of monozygotic twins, aged 54, who were diagnosed for diabetes type 2 ten years earlier. The first patient had trophic changes of muscles and skin tissues of the lower limb, and a necrotic wound on his right leg tibial region with the claudication distance of 50 m. After arteriography, he was referred by a vascular surgeon for hyperbaric oxygen therapy (HBO). HBO protocol implied 70 min. application of 100% oxygen at 2.5 absolute atmospheres. After the first series of HBO therapies consisting of 20 HBO treatments, claudication was eliminated and the necrotic wound healed. Next, surgical aortofemoral bypass was done. During the second HBO treatment, his monozygotic twin brother presented with angiopathic changes due to diabetes. In both patients, biochemical parameters corresponded to the expected level for diabetes type 2 imbalance, and the localization of the chromosomal defect (placed on 3, 11 and 19 chromosomal pair) was also in accordance with the respective disorder. After they were included into next 10 HBO treatments, Doppler imaging of the major arteries of limbs revealed normal findings. Identical genetic impairment in monozygotic twins can lead to identical somatic changes with resultant consequences. HBO treatment of such patients associated with other therapeutic procedures (conducted by diabetologist, vascular surgeon and physiatrist) can postpone or prevent irreversible changes occurring due to blood vessel disorders.

A sweet link between TGFβ and vascular disease?

Mutations in SCL2A10, encoding a glucose transporter, result in arterial tortuosity syndrome, indicating a link between glucose metabolism and angiopathic changes. Intriguingly, some of the phenotypic effects of SCL2A10 ablation may be mediated by upregulation of TGFβ signaling, suggesting new approaches for therapy of aortic aneurysm.

Retinopathy in Monkeys with Spontaneous Type 2 Diabetes

Type 2 diabetes occurs spontaneously in rhesus monkeys and shows an extraordinary similarity to human diabetes in clinical features and relative time course. The purpose of this study was to investigate clinically and histopathologically the ocular changes in these monkeys. Ophthalmoscopic examinations were performed on aged normal and diabetic monkeys. Retinas from 16 diabetic monkeys and 6 nondiabetic monkeys were incubated postmortem for adenosine diphosphatase (ADPase) activity (labels viable retinal blood vessels) and flat-embedded in JB-4. Tissue sections were cut through areas of interest. Cotton-wool spots, intraretinal hemorrhages, and hard exudates in the macula were observed by ophthalmoscopy in some diabetic monkeys. Dot/blot hemorrhages, cotton-wool spots, and small nonperfused areas were the earliest histologically documented changes in the retinas. Large nonperfused areas extending from optic disc to midfovea were observed in four diabetic monkeys. Formation of small intraretinal microvascular abnormalities (IRMAs) and microaneurysms were associated with the areas of nonperfusion. There were apparent fluid-filled spaces in the outer plexiform layer in three of these maculas, suggesting macular edema. There was a significant correlation between the occurrence of retinopathy and hypertension (P = 0.037 for systolic pressure; P = 0.019 for diastolic pressure). In elastase-digested retinas, the ratio of pericytes to endothelial cells was 0.66:1 in diabetic and 0.64:1 in nondiabetic (P = 0.75) retinas. This is the first detailed analysis of retinopathy in a colony of spontaneous type 2 diabetic monkeys. Monkeys with type 2 diabetes have many of the angiopathic changes associated with human diabetic retinopathy. Hypertension correlates with the severity of the diabetic retinopathy.

Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent ischemia-upregulated angiogenic protein that has been implicated in diabetic retinopathy. Intravitreal VEGF injections have not previously been shown to produce preretinal neovascularization. The purpose of this study was to further characterize the angiopathic changes that occur after intravitreal injections in a nonhuman primate and determine if preretinal neovascularization develops. DESIGN: Experimental animal study. METHODS: Vascular endothelial growth factor 165 was injected into the eyes of normal cynomolgus monkeys at regular intervals. As a control, normal eyes were injected with phosphate buffered saline. Color photography and fluorescein angiography were performed at regular intervals. The retinas were incubated for adenosine diphosphatase (ADPase) activity to visualize retinal vessels. The retinas were flat-embedded and areas of potential preretinal neovascularization were identified en bloc and serially sectioned. RESULTS: Areas of capillary nonperfusion and vessel dilation and tortuousity were seen by angiography. In serial sections, the nonperfused areas were found to be associated with endothelial cell hyperplasia in vessel lumens. Preretinal neovascularization originating only from superficial veins and venules was observed throughout peripheral retina, but was not seen in the posterior pole. Lacunae-like veins were subdivided by the process of intussusception and endothelial cell bridging. Arterioles demonstrated endothelial cell hyperplasia and microaneurysms. CONCLUSION: Intraocular injections of VEGF were sufficient to produce preretinal neovascularization in the nonhuman primate. Most vasculopathic structures were associated with endothelial cell hyperplasia. These results demonstrate that VEGF alone can produce many features of both nonproliferative and proliferative diabetic retinopathy including the previously undescribed development of preretinal neovascularization. This well-characterized VEGF-induced primate model of retinal neovascularization may be useful as a means of testing new treatments for retinal neovascularization.

Vascular endothelial growth factor and vascular permeability changes in human diabetic retinopathy: Kunz Mathews M, Merges C, McLeod DS, Lutty GA, Invest Ophthalmol Vis Sci 1997;38:2729–2741

The authors used histochemical analysis to determine whether increased vascular endothelial growth factor (VEGF) immunoreactivity in diabetic retinal vessels is related to increased vascular permeability, as indicated by human serum albumin (HSA) immunostaining, or to presumed retinal hypoxia as demonstrated by decreased vascularity. A correlation between VEGF and HSA in cryosections with angiopathic changes in the adenosine diphosphatase (ADPase) flat-embedded fellow retinas was sought. Because VEGF is a heparin-binding protein, the relation between VEGF and heparan sulfate proteoglycan (HSPG) immunoreactivities was also investigated.Cryopreserved eyes from 18 diabetic and 9 nondiabetic subjects removed after death were sectioned and immunohistochemical analysis was performed with antibodies against VEGF, HSA, HSPG, vWf (von Willebrand factor), and collagen IV. The fellow retinas were prepared by our ADPase flat-embedding technique to determine the degree of diabetic retinopathy. The number of positive vessels for each antibody and antibody localizations were determined by light microscopy.The average number of VEGF-stained vessels in diabetic retinas was significantly higher than in nondiabetic retinas (P = 0.04). In diabetic retinas, there was a positive correlation between the distribution of VEGF-positive vessels and the distribution of HSA- and HSPG-positive vessels. No such correlation was observed in nondiabetic eyes. In many cases, HSPG immunoreactivity appeared colocalized with VEGF immunoreactivity, suggesting VEGF binding to HSPG. The comparison with the ADPase flat-embedded fellow retinas suggested that increased VEGF immunoreactivity and vascular permeability may occur before morphologic changes in the vasculature.Vascular endothelial growth factor immunoreactivity was correlated with increased vascular permeability to macromolecules and appears to be increased in diabetic subjects before the onset of retinopathy.

Angioarchitecture of the atrophic pancreas.

The pancreas has a complex vasculature which comprises both exocrine and endocrine structures. Copper deficiency induces highly selective acinar cell degeneration and progressive noninflammatory lipomatosis in pancreas while Langerhans islets, ducts, and nerves remain unaffected. Pancreatic vasculature was examined in rats that had dietary copper deficiency to characterize changes in the angioarchitecture of the gland. This model was used to assess the degree to which the vasculature of non-acinar components of the gland are potentially altered under conditions of exocrine atrophy. Ultrastructure of pancreas was examined by histology, enzyme histochemistry and immunohistochemistry, corrosion casting and scanning electron microscopy, in situ vascular staining, microsphere injection, biochemical analysis, and morphometry in copper-deficient rats. Results show that no acute angiopathic changes indicative of vascular disorganization accompany atrophy. Only a reduction in the complexity of the capillary beds, which normally vascularize the dense acinar parenchyma, was found. Microsphere quantitation also showed that blood flow to the lipomatous gland remains intact. Furthermore, analysis of the angioarchitecture of the atrophied pancreas supports a largely autonomous blood supply to islets and ducts. These observations support the hypothesis that while the vasculature of the atrophied gland is modified in vascular regions severely targeted by acinar necrosis, the overall structural features of the angioarchitecture are preserved. The atrophied gland thus provides an experimental model to study the vascular routes supplying islet and ductal blood flow within the complex pancreatic circulation.

Angioarchitecture of the atrophic pancreas

The pancreas has a complex vasculature which comprises both exocrine and endocrine structures. Copper deficiency induces highly selective acinar cell degeneration and progressive noninflammatory lipomatosis in pancreas while Langerhans islets, ducts, and nerves remain unaffected. Pancreatic vasculature was examined in rats that had dietary copper deficiency to characterize changes in the angioarchitecture of the gland. This model was used to assess the degree to which the vasculature of non-acinar components of the gland are potentially altered under conditions of exocrine atrophy. Ultrastructure of pancreas was examined by histology, enzyme histochemistry and immunohistochemistry, corrosion casting and scanning electron microscopy, in situ vascular staining, microsphere injection, biochemical analysis, and morphometry in copper-deficient rats. Results show that no acute angiopathic changes indicative of vascular disorganization accompany atrophy. Only a reduction in the complexity of the capillary beds, which normally vascularize the dense acinar parenchyma, was found. Microsphere quantitation also showed that blood flow to the lipomatous gland remains intact. Furthermore, analysis of the angioarchitecture of the atrophied pancreas supports a largely autonomous blood supply to islets and ducts. These observations support the hypothesis that while the vasculature of the atrophied gland is modified in vascular regions severely targeted by acinar necrosis, the overall structural features of the angioarchitecture are preserved. The atrophied gland thus provides an experimental model to study the vascular routes supplying islet and ductal blood flow within the complex pancreatic circulation. Microsc. Res. Tech. 37:520–542, 1997. © 1997 Wiley-Liss, Inc.

2-Chloro-2' deoxyadenosine prevents angiopathic changes in cerebral arteries in experimental SAH in rabbits.

We compared the morphology of the basilar artery walls in rabbits with experimental subarachnoid haemorrhage (SAH) without and with concomitant treatment with a novel immunosuppressive drug, 2-chloro-2'-deoxyadenosine (2 CdA). The treatment was successful in the prevention of the angiopathic changes, most likely due to its ability to inhibit lymphocyte activation in response to mitogenic signals. Since lymphocyte (and monocyte?) activation may play an important role in the development of the delayed neurological deficits in patients following SAH, the use of 2 CdA to prevent these deficits shall be considered.

Immunomodulators interfere with angiopathy but not vasospasm after subarachnoid haemorrhage in rabbits

The present study deals with the effects of immunomodulators on the morphology of intracerebral arterial walls in rabbits with experimental subarachnoid haemorrhage (SAH). Immunostimulators:thymostimuline and inosine dimethylamino-isopropanol-p-acetamido-benzoate were found to aggravate the angiopathic changes, whereas immunosuppressive drugs-cyclosporine A and azathioprine appeared to prevent the damage. The authors consider the possibility of using immunosuppressive drugs in patients with ruptured intracranial aneurysms.

Progressive changes in pancreatic vasculature accompanying copper deficiency-induced glandular atrophy.

Pancreatic vasculature was studied in rats treated with a dietary copper-deficient regimen to assess and characterize changes in the exocrine angioarchitecture of the gland. The deficient state is known to induce progressive acinar degeneration, atrophy, and subsequent replacement with noninflammatory lipomatosis. This study was carried out since little information exists regarding changes in the vasculature that accompany acute glandular necrosis. Corrosion casts produced from Mercox injected deficient rats were studied using scanning electron microscopy and compared to injected preparations studied by light microscopy. Results show that with initial atrophy of degenerative acini (6-8 wk), pancreatic lobules decreased in size and the volume of the vascular bed reduced. From wk 8 onward, the accumulation of fat cells expanded the configuration of lobules to more normal dimensions. Although vascular interconnectivity within lobules remained reduced, its basic angioarchitecture remained intact and served to vascularize fat cells in lieu of acini. No acute angiopathic changes indicative of vascular disorganization were found. These observations support the hypothesis that the vasculature of the atrophied pancreas, although modified in regions of the gland most severely targeted by acinar necrosis, remains intact and its basic structural features preserved. Preliminary evidence also supports the observation that preservation of the basic elements of lobular angioarchitecture may form the basis for subsequent regeneration of acinar tissue in the reversed deficient state.