青光眼药物对眼部血液循环的影响

尽管眼压被认为是青光眼发病的主要危险因素,越来越多的证据显示,眼部缺血也对青光眼发病起着重要作用。由于当前所用的许多青光眼药物对血管系统有影响,因此评价这些药物对眼部循环的作用有着重要意义。本文就6大类局部降眼压药物对眼血流的影响进行综述。     

The role of blood pressure in glaucoma

Although intraocular pressure (IOP) remains an important risk factor for glaucoma, it is clear that other factors can also influence disease development and progression. More recently, the role that blood pressure (BP) has in the genesis of glaucoma has attracted attention, as it represents a clinically modifiable risk factor and thus provides the potential for new treatment strategies beyond IOP reduction. The interplay between blood pressure and IOP determines the ocular perfusion pressure (OPP), which regulates blood flow to the optic nerve. If OPP is a more important determinant of ganglion cell injury than IOP, then hypotension should exacerbate the detrimental effects of IOP elevation, whereas hypertension should provide protection against IOP elevation. Epidemiological evidence provides some conflicting outcomes of the role of systemic hypertension in the development and progression of glaucoma. The most recent study showed that patients at both extremes of the blood pressure spectrum show an increased prevalence of glaucoma. Those with low blood pressure would have low OPP and thus reduced blood flow; however, that people with hypertension also show increased risk is more difficult to reconcile. This finding may reflect an inherent blood flow dysregulation secondary to chronic hypertension that would render retinal blood flow less able to resist changes in ocular perfusion pressure. Here we review both clinical and experimental studies that have attempted to clarify the relationships among blood pressure, OPP and blood flow autoregulation in the pathogenesis of glaucoma.     

Vascular Aspects in the Pathophysiology of Glaucomatous Optic Neuropathy

Glaucoma remains a major eye illness with unknown etiology. Although elevated intraocular pressure is clearly a major risk factor, vascular deficits may contribute to initiation and progression of glaucoma. When intraocular pressure is acutely elevated in healthy individuals, the resistance index (derived from the peak systolic and end-diastolic velocities and an indirect index of vascular resistance distal to the site of measurement) in the central retinal and posterior ciliary arteries increases progressively. This result implies that mechanical and vascular factors may be coupled in such a way that perfusion of the retina and optic nerve head may be influenced by changes in the intraocular pressure. Further, at night, when ophthalmic artery flow velocities fall as arterial blood pressure falls in glaucoma patients, the risk of disease progression may be increased. The constancy of these same flow velocities in age-matched healthy individuals points to a possible vascular autoregulatory defect in glaucoma. In addition, in normal-tension glaucoma, vasodilation (CO₂ inhalation) normalizes retrobulbar arterial flow velocities, hinting that some vascular deficits in glaucoma may be reversible. Finally, Ca²+ channel blockade improves contrast sensitivity in patients with normal-tension glaucoma, who also show increased retrobulbar vessel flow velocities, a result suggesting that visual function loss may be linked to ocular ischemia. Emerging evidence points to a role of ischemia in the pathogenesis of glaucoma, suggesting that treatments designed to improve ocular blood flow may benefit glaucoma patients.     

Alteration in ocular blood flow and its effect on the progression of glaucoma

青光眼是由多种因素引起的神经退行性疾病,眼压过高会损害视神经而导致永久性视力丧失。虽然青光眼的基本病理生理机制尚未确定,但眼组织如视神经,视网膜,脉络膜以及虹膜的血流改变是青光眼发病的重要危险因素。由于不同因素所引发的视神经损害的有限认知,测量方法和治疗方面缺乏,人们对青光眼的理解存在障碍。尽管研究人员在不断地积累证据,力证眼血流的变化在青光眼发病机制中起着重要的作用,但大部分情况下,对于眼血流的变化和青光眼的患病风险之间的关系,他们都持有多样甚至矛盾的结论。本文中,我们回顾了青光眼的不同方面以及眼血流在疾病发展中的影响。     

The impact of ocular blood flow in glaucoma

Two principal theories for the pathogenesis of glaucomatous optic neuropathy (GON) have been described--a mechanical and a vascular theory. Both have been defended by various research groups over the past 150 years. According to the mechanical theory, increased intraocular pressure (IOP) causes stretching of the laminar beams and damage to retinal ganglion cell axons. The vascular theory of glaucoma considers GON as a consequence of insufficient blood supply due to either increased IOP or other risk factors reducing ocular blood flow (OBF). A number of conditions such as congenital glaucoma, angle-closure glaucoma or secondary glaucomas clearly show that increased IOP is sufficient to lead to GON. However, a number of observations such as the existence of normal-tension glaucoma cannot be satisfactorily explained by a pressure theory alone. Indeed, the vast majority of published studies dealing with blood flow report a reduced ocular perfusion in glaucoma patients compared with normal subjects. The fact that the reduction of OBF often precedes the damage and blood flow can also be reduced in other parts of the body of glaucoma patients, indicate that the hemodynamic alterations may at least partially be primary. The major cause of this reduction is not atherosclerosis, but rather a vascular dysregulation, leading to both low perfusion pressure and insufficient autoregulation. This in turn may lead to unstable ocular perfusion and thereby to ischemia and reperfusion damage. This review discusses the potential role of OBF in glaucoma and how a disturbance of OBF could increase the optic nerve's sensitivity to IOP.     

Blood flow in glaucoma

PURPOSE OF REVIEW: Glaucoma, one of the leading causes of blindness in the world, is characterized by progressive visual field loss and distinctive excavation of the optic nerve head. Although elevated intraocular pressure is the major risk factor, there is increasing evidence that the pathogenesis of glaucoma is also linked to altered ocular blood flow. This review summarizes the recent publications relevant to blood flow in glaucoma. RECENT FINDINGS: Several studies indicate that a perfusion instability, rather than a steady reduction of ocular blood flow, might contribute to glaucomatous optic neuropathy. The main cause of the instability is a disturbed autoregulation in the context of a general vascular dysregulation. The underlying mechanism of such a vascular dysregulation is not known. A dysfunction of both the autonomic nervous system and vascular endothelial cells is discussed. SUMMARY: The mechanical and vascular theories are not mutually exclusive; on the contrary, a vascular dysregulation increases the susceptibility to intraocular pressure. Therapeutically, therefore, both an intraocular pressure reduction and an improvement of the ocular blood flow might be considered.     

Endothelial dysfunction in glaucoma

Glaucoma is a group of ocular diseases characterized by optic neuropathy associated with loss of the retinal nerve fibre layer and re‐modelling of the optic nerve head, and a subsequent particular pattern of visual field loss. Increased intraocular pressure is the most important risk factor for the disease, but the pathogenesis of glaucoma is not monofactorial. Among other factors, ischaemia and vascular dysregulation have been implicated in the mechanisms underlying glaucoma. The vascular endothelium plays an important role in the regulation of ocular blood flow and pathological alterations of vascular endothelial cells may induce ischaemia and dysregulation. The present review summarizes our current evidence of endothelial dysfunction in glaucoma. This is of interest because endothelial dysfunction is a good prognostic factor for progression in several diseases. Although such data are lacking for glaucoma, endothelial dysfunction may provide an attractive target for therapeutic intervention in open‐angle glaucoma and other vascular disorders of the eye.     

The Role of Inflammation in the Pathogenesis of Glaucoma

Glaucoma is an ocular disorder characterized by the progressive loss of retinal ganglion cells (RGC) and their axons. There are various hypotheses concerning the cause of RGC death. Previously, glaucoma was defined by high intraocular pressure (IOP); during the past decade, however, glaucoma specialists have acknowledged that elevated IOP is the most important risk factor for glaucoma, but does not define the disease. Other factors such as genetics, blood flow, and excitotoxicity are suggested as potential causal factors for progressive RGC death observed in glaucoma. We review recent studies elucidating a possible role of low-grade inflammation as a causal factor in the pathogenesis of glaucoma.     

Abnormalities of microcirculation in glaucoma: facts and hints

Many risk factors associated with glaucoma have been identified recently. The best known of these is increased intraocular pressure (IOP). Among the others, however, vascular risk factors play a major role. Although such vascular factors were already postulated more than 100 years ago, only recent technical developments have afforded systematic investigations of associated microcirculatory disturbances and basic principles of blood flow regulation. In glaucoma, besides IOP, vascular dysregulation (such as local vasospasm and systemic hypotension, resulting in impaired autoregulation of blood flow in the optic nerve head, the choroid, and other ocular tissues) seems to be a major risk factor. However, multiple coacting factors, which are not limited to the eye but are, rather, symptoms of a systemic disease, seem to be involved in the damaging process.     

Primary open-angle glaucoma and systemic diseases

The exact pathomechanism of primary open-angle glaucoma (POAG) is still not completely understood. Besides elevated intraocular pressure, which has been identified as a major risk factor, there is mounting evidence for the involvement of systemic factors in the development of glaucomatous damage. Systemic peculiarities described in POAG include cardiovascular, endocrine, neurodegenerative, and sleep alterations. However, some of the studies available on systemic findings in glaucoma patients are contradictory, making further research necessary to identify the exact role of such disturbances in the pathogenesis of the damage. Another difficulty is that many studies are limited by their small sample size, their retrospective nature, and potential selection bias, thus making data interpretation more difficult. Moreover, it is not always clear whether we are dealing with coincidence or a true association between glaucoma and a particular systemic disease. Nevertheless, there is ample evidence for the involvement of vascular factors such as vascular dysregulation and blood pressure in the pathogenesis of POAG.     

Primäres Offenwinkelglaukom und Allgemeinerkrankungen

The exact pathomechanism of primary open-angle glaucoma (POAG) is still not completely understood. Besides elevated intraocular pressure, which has been identified as a major risk factor, there is mounting evidence for the involvement of systemic factors in the development of glaucomatous damage. Systemic peculiarities described in POAG include cardiovascular, endocrine, neurodegenerative, and sleep alterations. However, some of the studies available on systemic findings in glaucoma patients are contradictory, making further research necessary to identify the exact role of such disturbances in the pathogenesis of the damage. Another difficulty is that many studies are limited by their small sample size, their retrospective nature, and potential selection bias, thus making data interpretation more difficult. Moreover, it is not always clear whether we are dealing with coincidence or a true association between glaucoma and a particular systemic disease. Nevertheless, there is ample evidence for the involvement of vascular factors such as vascular dysregulation and blood pressure in the pathogenesis of POAG.     

The complex interaction between ocular perfusion pressure and ocular blood flow – Relevance for glaucoma

Glaucoma is an optic neuropathy of unknown origin. The most important risk factor for the disease is an increased intraocular pressure (IOP). Reducing IOP is associated with reduced progression in glaucoma. Several recent large scale trials have indicated that low ocular perfusion pressure (OPP) is a risk factor for the incidence, prevalence and progression of the disease. This is a strong indicator that vascular factors are involved in the pathogenesis of the disease, a hypothesis that was formulated 150 years ago. The relation between OPP and blood flow to the posterior pole of the eye is, however, complex, because of a phenomenon called autoregulation. Autoregulatory processes attempt to keep blood flow constant despite changes in OPP. Although autoregulation has been observed in many experiments in the ocular vasculature the mechanisms underlying the vasodilator and vasoconstrictor responses in face of changes in OPP remain largely unknown. There is, however, recent evidence that the human choroid regulates its blood flow better during changes in blood pressure induced by isometric exercise than during changes in IOP induced by a suction cup. This may have consequences for our understanding of glaucoma, because it indicates that blood flow regulation is strongly dependent not only on OPP, but also on the level of IOP itself. Indeed there is data indicating that reduction of IOP by pharmacological intervention improves optic nerve head blood flow regulation independently of an ocular vasodilator effect.     

Comparative assessment of hemodynamic risk factors of glaucomatous optic neuropathy progress

Comparative evaluation of the significance of hemodynamic factors of risk of progress of glaucomatous optic neuropathy has been carried out: blood flow velocity, blood flow resistance, blood pressure in the orbital artery-central retinal artery system, perfusion ocular pressure in connection with stabilization of glaucomatous process, and intraocular pressure were analyzed for a period of up to 16 years. The most significant factors were blood pressure in the orbital artery-central retinal artery system and perfusion ocular pressure, but not blood flow velocity. The leading factor indicating the risk of progress of optic neuropathy in primary glaucoma is ocular perfusion pressure. Measurements of opthalmodynamometric pressure can be used for evaluation of perfusion pressure and recommended for wide clinical application for predicting the course of primary glaucoma.     

The Circadian Variations in Systemic Blood Pressure, Ocular Perfusion Pressure, and Ocular Blood Flow: Risk Factors for Glaucoma?

Intraocular pressure, a major risk factor for glaucoma, is known to vary throughout the day, yet glaucoma continues to progress in some patients despite it being well controlled. It is important to understand how other glaucomatous risk factors are affected by circadian variations. The purpose of this review is to analyze the literature concerning circadian variations in systemic blood pressure, ocular perfusion pressure, and ocular blood flow and to identify consensus findings regarding their impact on glaucoma. This review suggests that nonphysiologic nocturnal blood pressure dipping and wider circadian fluctuations in ocular perfusion pressure are linked with the development and progression of glaucoma. No consensus concerning circadian variations in ocular blood flow exists in the current literature, and future investigations of nocturnal changes in blood flow and glaucoma progression are required.     

Vascular risk factors for primary open angle glaucoma: the Egna-Neumarkt Study

OBJECTIVE: To assess the impact of vascular risk factors on the prevalence of primary open angle glaucoma. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Four thousand two hundred ninety-seven patients more than 40 years of age underwent a complete ocular examination in the context of the Egna-Neumarkt Glaucoma Study. INTERVENTION: Ocular examinations were performed by trained, quality-controlled ophthalmologists according to a predefined standardized protocol including medical interview, blood pressure reading, applanation tonometry, computerized perimetry, and optic nerve head examination. MAIN OUTCOME MEASURES: Prevalences of ocular hypertension, primary open-angle glaucoma, normal-tension glaucoma, and other types of glaucoma were determined. Correlation coefficients were calculated for the association between systemic blood pressure and age-adjusted intraocular pressure (IOP) and between age and both intraocular and systemic blood pressures. Odds ratios were computed to assess the risk of primary open-angle glaucoma and normal-tension glaucoma in relation to systemic hypertension or antihypertensive medication, blood pressure levels, diastolic perfusion pressure, and a number of other cardiovascular risk factors. RESULTS: A positive correlation was found between systemic blood pressure and IOP, and an association was found between diagnosis of primary open-angle glaucoma and systemic hypertension. Lower diastolic perfusion pressure is associated with a marked, progressive increase in the frequency of hypertensive glaucoma. No relationship was found between systemic diseases of vascular origin and glaucoma. CONCLUSIONS: Our data are in line with those reported in other recent epidemiologic studies and show that reduced diastolic perfusion pressure is an important risk factor for primary open-angle glaucoma.     

Relationships among systemic blood pressure, intraocular pressure, and open-angle glaucoma

Several vascular factors, including systemic hypertension (or high blood pressure [HBP]), ocular perfusion pressure, and nocturnal hypotension, have been identified as risk factors for the development and progression of glaucoma. The results of epidemiologic studies of these factors and their relationships to intraocular pressure (IOP) and open-angle glaucoma (OAG) have been contradictory. Inconsistent definitions of HBP and OAG, inconsistent design, and differing population characteristics within these studies have obfuscated definitive conclusions. Here, we review the relationships among blood pressure, IOP, and OAG.     

眼减压性视网膜病变研究进展

眼减压性视网膜病变(ocular decompression retinopathy,ODR)是一种由眼压降低引起的眼底多灶性出血性视网膜病变,且无法用其他机制解释。临床上多见于青光眼术后,也可发生在造成眼压下降的其他眼科手术。多数患者无明显症状,容易漏诊。本文综述了国内外ODR的研究进展,从危险因素、发病机制、临床表现、影像表现、鉴别诊断以及治疗与预防来论述。     

Ocular blood flow as a clinical observation: Value,limitations and data analysis

Alterations in ocular blood flow have been identified as important risk factors for the onset and progression of numerous diseases of the eye. In particular, several population-based and longitudinal-based studies have provided compelling evidence of hemodynamic biomarkers as independent risk factors for ocular disease throughout several different geographic regions. Despite this evidence, the relative contribution of blood flow to ocular physiology and pathology in synergy with other risk factors and comorbidities (e.g., age, gender, race, diabetes and hypertension) remains uncertain. There is currently no gold standard for assessing all relevant vascular beds in the eye, and the heterogeneous vascular biomarkers derived from multiple ocular imaging technologies are non-interchangeable and difficult to interpret as a whole. As a result of these disease complexities and imaging limitations, standard statistical methods often yield inconsistent results across studies and are unable to quantify or explain a patient's overall risk for ocular disease.Combining mathematical modeling with artificial intelligence holds great promise for advancing data analysis in ophthalmology and enabling individualized risk assessment from diverse, multi-input clinical and demographic biomarkers. Mechanism-driven mathematical modeling makes virtual laboratories available to investigate pathogenic mechanisms, advance diagnostic ability and improve disease management. Artificial intelligence provides a novel method for utilizing a vast amount of data from a wide range of patient types to diagnose and monitor ocular disease. This article reviews the state of the art and major unanswered questions related to ocular vascular anatomy and physiology, ocular imaging techniques, clinical findings in glaucoma and other eye diseases, and mechanistic modeling predictions, while laying a path for integrating clinical observations with mathematical models and artificial intelligence. Viable alternatives for integrated data analysis are proposed that aim to overcome the limitations of standard statistical approaches and enable individually tailored precision medicine in ophthalmology.     

Ocular blood flow and systemic blood pressure in patients with primary open-angle glaucoma and ocular hypertension

PURPOSE: There is evidence that altered optic nerve head (ONH) blood flow may play a role in the development and progression of glaucoma. In the present study, the baseline characteristics were examined in a study population participating in a clinical trial in which the ocular hemodynamic effects of timolol and dorzolamide were compared. METHODS: One hundred forty patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT) were included in this trial and their baseline parameters compared with those of a group of 102 age-matched control subjects. Scanning laser Doppler flowmetry was used to measure blood flow in the temporal neuroretinal rim and the cup of the ONH. Pulsatile choroidal blood flow was assessed by laser interferometric measurement of fundus pulsation amplitude. In addition, hemodynamic parameters and mean arterial pressure were calculated in both groups. RESULTS: All ocular hemodynamic parameters were significantly lower in the POAG/OHT group compared with the healthy control group (P < 0.001 each). In addition, a significant positive correlation between laser Doppler flowmetry readings and mean arterial pressure was observed in patients with glaucoma but not in healthy control subjects. Likewise, the correlation coefficient between fundus pulsation amplitude and mean arterial pressure was higher in patients with glaucoma than in healthy control subjects. CONCLUSIONS: The present study indicates reduced ONH and choroidal blood flow and an abnormal association between blood pressure and ocular perfusion in patients with primary open-angle glaucoma or ocular hypertension, independent of topical antiglaucoma medication. Hence, vascular dysregulation appears to be an early manifestation in glaucoma that is not caused by pharmacologic intervention.     

Neuroprotection in glaucoma

Neuroprotective therapies in glaucoma may play a role in preventing ischemia and oxidative damage that results in apoptosis of retinal ganglion cells and optic nerve damage. Although intraocular pressure (IOP) is the only known modifiable risk factor for glaucoma, disease progression commonly occurs despite IOP control, suggesting that factors other than IOP play a role in its pathogenesis and can potentially act as targets for neuroprotection. Factors including mediators of apoptosis, ischemic changes, poor ocular blood flow and neurotoxins have been hypothesized to play a role in glaucoma progression. Neuroprotective targets include glutamate-induced neurotoxicity, nitric oxidase synthetase, neurotropins, calcium channel receptors, free radicals, vascular insufficiency, the rho-kinase pathway, and more. Drugs related to these factors are being evaluated for their role in neuroprotection, although this area of investigation faces several challenges including limited evidence for these agents’ efficacy in clinical studies. Additionally, while IOP-lowering therapies are considered neuroprotective as they generally slow the progress of glaucoma progression, they are limited by the extent of their effect beyond IOP control. The aim of this article is to review the current treatment options available for neuroprotection and to explore the drugs in the pipeline.