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.     

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.     

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.     

原发性开角型青光眼进展的危险因素研究概况

原发性开角型青光眼(POAG)进展的危险因素包括全身性及眼部因素,眼部因素包括眼压及非眼压因素.在以往的多中心研究中,眼压对于由高眼压症发展为POAG及其在POAG进展中的作用已经明确,而目前降低眼压也是临床惟一有效地延缓、控制青光眼视神经损害进展的主要因素.制定目标眼压,进行降眼压治疗尤其是控制昼夜眼压波动对于阻止青光眼进展非常重要.非眼压危险因素包括高龄、中央角膜厚度增厚、视乳头出血、晶状体囊膜剥脱征、初始的青光眼严重程度及双眼罹患青光眼等.其他因素包括近视、青光眼家族史、眼部低灌注压、低血压、心血管疾病、高血压、高血脂等血管或血液性因素.POAG进展的危险因素研究在一定程度上揭示了POAG的发病机制及临床发病规律,对于指导临床医师决定随诊频率、选择治疗方案及提高治疗效率意义重大.     

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.     

Associations with intraocular pressure in Latinos: the Los Angeles Latino Eye Study

PURPOSE: To evaluate the association of biologic factors with intraocular pressure (IOP) in a Latino population. DESIGN: Population-based cross-sectional study. METHODS: Latinos 40 years and older (n = 5,958) from the Los Angeles Latino Eye Study without a history of ocular hypotensive treatment underwent an interviewer-administered questionnaire and a complete ocular and clinical examination. IOP was obtained by applanation tonometry and was based on the mean of three measurements. Multivariable regression models were used to evaluate the independent association of biological factors with IOP. RESULTS: Higher systolic blood pressure, higher central corneal thickness, and diabetes mellitus were the major factors associated with elevated IOP. Other positively correlated variables included age, female gender, higher diastolic blood pressure, larger body mass index, darker colored irides, and nuclear sclerosis. Axial length and family history of glaucoma had no association with IOP. CONCLUSIONS: Several systemic and ocular characteristics are associated with elevated IOP in Latinos. By identifying and recognizing these risk factors, we can define subgroups of the population that may be most at risk of having elevated IOP.     

Einfluss des Liquordrucks auf die glaukomatöse Schädigung des Nervus opticus

Eyes with normal pressure glaucoma and eyes with high pressure glaucoma show a similar optic disc appearance with marked differences to eyes with vascular optic neuropathy. Non-vascular, potentially barotraumatic factors in addition to intraocular pressure (IOP) may thus play a role in glaucoma. Recent studies have shown that cerebrospinal fluid pressure (CSFP), arterial blood pressure and IOP are correlated with each other, higher CSFP is associated with younger age, higher blood pressure and higher body mass index, some patients with normal (IOP) pressure glaucoma have abnormally low CSFP and thus an abnormally high trans-lamina cribrosa pressure difference and a small orbital CSF space, the orbital CSF space width is associated with CSFP and the estimated CSFP correlated better with open-angle glaucoma-related parameters than IOP. The orbital CSFP as counter-pressure against IOP may play a role in the pathogenesis of glaucoma.     

Vascular risk factors in glaucoma: a review

Glaucoma, one of the major causes of blindness in the world, is a progressive optic neuropathy. Elevated intraocular pressure is a well-known major risk factor for glaucoma. In addition, there is growing evidence that vascular factors may play a role in glaucoma pathogenesis. Systemic (e.g. hypertension, diabetes) and ocular vascular factors (e.g. ocular blood flow, ocular perfusion pressure) have been assessed for associations with glaucoma. However, direct and convincing evidence for primary mechanisms of glaucoma is still lacking. The aim of this review is to summarize the evidence implicating vascular factors in the pathogenesis of glaucoma, with particular emphasis on the role of ocular blood flow and ocular circulation as risk factors for primary open angle glaucoma.     

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.     

Glaucoma and obstructive sleep apnoea syndrome

Glaucoma is increasingly recognized as a manifestation of both ocular and systemic risk factors. A number of disorders associated with reduced blood flow and ischaemia, collectively termed vascular risk factors, such as migraine, Raynaud's phenomenon, atrial fibrillation and reduced nocturnal blood pressure, lead to decreased ocular perfusion pressure. During sleep, alterations occur in cardiovascular physiology that are balanced by autoregulation to maintain homeostasis. However, in obstructive sleep apnoea (OSA), the normal physiological balance is upset. A potentially modifiable risk factor, OSA has been increasingly associated with glaucoma independent of intraocular pressure. OSA may alter blood flow to the optic nerve head and, in combination with other predisposing factors, lead to decreased ocular perfusion pressure. This in turn may directly affect the optic nerve or it may indirectly increase its susceptibility to other insults. The purpose of this review is to shed light on the association between OSA and glaucoma.     

Relative risk factors in chronic open-angle glaucoma: an epidemiological study.

Some hypothesized risk factors in chronic open-angle glaucoma were investigated in a sample of 87 patinets with glaucoma and 87 matched controls. A significant positive association was found with diabetes, a systolic blood pressure/intraocular pressure (BP/IOP) ratio less than 5.75, and the taking of medication for systemic hypertension. No significant association was found with a history of smoking or an elevated systemic blood pressure. Analysis indicates that the systolic BP/IOP index may be useful as a screening test for the detection of glaucoma in samples where the prevalence of glaucoma is high.     

正常眼压性青光眼与视盘血流灌注的关系

正常眼压性青光眼（normal tension glaucoma, NTG）是青光眼中的特殊类型,发病隐匿,机制未明,可能与视神经乳头血流灌注异常有关,如系统性低血压、全身或局部血管狭窄、眼部血流量下降、视神经乳头血流调控异常等,并最终导致视乳头和巩膜筛板血流灌注降低,发生NTG。（国际眼科纵览,2019, 43： 411-415）     

Socioeconomic status, systolic blood pressure and intraocular pressure: the Tanjong Pagar Study

BACKGROUND: Lower socioeconomic status (SES) is associated with higher morbidity and mortality in many countries. Present evidence suggests that glaucoma has similar risk factors to major chronic diseases such as cardiovascular disease. This study investigates the association between SES and intraocular pressure (IOP), an important risk factor for glaucoma. METHODS: The Tanjong Pagar Study was a population-based cross-sectional survey of Chinese people aged 40-79 years, who were randomly selected from the Singapore electoral register. Of the 2000 people selected, 1717 were considered eligible and 1090 were examined in clinic and included in the present study. IOP was measured using applanation tonometry. SES was assessed using a standardised questionnaire; education and income were used as the main explanatory variables. The effect of systolic blood pressure (SBP) was also examined. RESULTS: Participants with lower levels of education and income had higher mean IOP (both p<0.01). These associations remained after adjusting for age and central corneal thickness, a strong independent predictor. SBP was strongly associated with both SES and IOP (both p<0.01). Adjusting for SBP attenuated the association between SES and IOP. CONCLUSION: Participants with lower education and income have a higher mean IOP. This effect may be mediated, in part, by an association of education and income with SBP. This is the first study to suggest that there is a social gradient in the distribution of the only major modifiable risk factor for glaucoma. Increasing similarities exist between the causation models of chronic diseases and that of glaucoma.     

Retinal ganglion cells death in glaucoma--mechanism and potential treatment. Part I

Glaucoma is a kind of optic neuropathy where selective retinal ganglion cell loss is the major hallmark. Frequently glaucoma is associated with elevated intraocular pressure, but this condition is neither necessary nor sufficient for onset and progression of the disease. The exact mechanism of ganglion cell death in glaucoma and fully effective treatment of glaucomatous neuropathy still remain unknown. This article is a review of the recent researches relevant to IOP independent risk factors, mechanisms of RGC death and modern potential therapeutic strategies in glaucoma. Part one includes review of blood flow changes, neurotrophic factors deprivation and apoptotic dysregulation findings in glaucoma.     

Cod liver oil: a potential protective supplement for human glaucoma

Glaucoma is one of the leading causes of visual impairment and blindness. Improved knowledge of the pathogenesis of this disease has allowed the exploration of new therapeutic methods. In general, elevated intraocular pressure (IOP), oxidative stress, and vascular insufficiency are accepted as the major risk factors for the progression of glaucoma. Many natural compounds have been found beneficial for glaucoma. Nutritional therapies are now emerging as potentially effective in glaucomatous therapy. One nutritional supplement with potential therapeutic value is cod liver oil, a dietary supplement that contains vitamin A and omega-3 polyunsaturated fatty acids (PUFAs). Vitamin A is important for preserving normal vision and it is a well-known antioxidant that prevents the oxidative damage that contributes to the etiology and progression of glaucoma. Vitamin A is also a crucial factor for maintaining the integrity of conjunctival and corneal ocular surfaces, and preventing the impairment of ocular epithelium caused by topical antiglaucomatous drugs. Omega-3 fatty acids are beneficial for glaucoma patients as they decrease IOP, increase ocular blood flow, and improve optic neuroprotective function. In this article, we propose that cod liver oil, as a combination of vitamin A and omega-3 fatty acids, should be beneficial for the treatment of glaucoma. However, further studies are needed to explore the relationship between cod liver oil and glaucoma.     

Retrobulbar blood flow in glaucoma patients with nocturnal over-dipping in systemic blood pressure.

PURPOSE: To evaluate the relationship between the circadian blood pressure rhythm and the retrobulbar blood flow in glaucoma patients. DESIGN: Cross-sectional study. METHODS: Circadian blood pressure measurements and color Doppler imaging (CDI) in the ophthalmic artery as well as the central retinal artery of one randomly selected eye were obtained in 193 primary open-angle glaucoma patients. CDI parameters were compared by means of analysis of covariance between patients with a nocturnal decrease in mean systemic blood pressure (MBP) below 20% of the average daytime MBP (over-dippers), patients with a decrease between 10% to 20% (dippers), and patients with a decrease of less than 10% (nondippers), using age, intraocular pressure (IOP), and MBP during color Doppler measurement as covariates. RESULTS: An analysis of covariance disclosed, after correcting for age, IOP, and MBP during color Doppler imaging, a significantly lower EDV (P =.0096) and a significantly higher RI (P =.033) in the central artery of over-dipping glaucoma patients compared with nondippers or dippers. This effect seemed independent of the use of vasoactive drugs .CONCLUSIONS: Glaucoma patients with a marked drop in nocturnal systemic blood pressure seem to have altered retrobulbar blood flow parameters, suggesting that an abnormal systemic blood pressure profile may be the manifestation of some kind of systemic vascular dysregulation relevant for the ocular circulation.     

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.     

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.     

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.