Unraveling the complex role of perfusion pressure in glaucoma progression

Bloomington, IN-The understanding of the etiology of glaucoma has come a long way since the time that IOP was considered the sole determinant of glaucomatous damage. 

Investigators currently are on the threshold of uncovering the complex relationships in the eye that govern the development and progression of glaucoma.

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Perfusion pressure is another factor that has recently began to come under closer scrutiny. In the eye, according to Alon Harris, MS, PhD, FARVO, ocular perfusion pressure can be calculated by the formula 2/3 of the mean arterial pressure minus the IOP.

“The difference between IOP and blood pressure is critical when talking about the driving force of the perfusion pressure,” said Dr. Harris, director of clinical research, Lois Letzter professor of ophthalmology, professor of Ccellular and integrative physiology, within the department of ophthalmology, at Indiana University School of Medicine, Bloomington, IN.

Dr. Harris discussed the relationship among different variables that affect the perfusion pressure, specifically the IOP, blood pressure, and the combination of the two, the weight of each variable, and whether it the same across the entire IOP spectrum.

“These are important clinical questions,” he said.

Evaluation

Dr. Harris and his colleagues have embarked upon development and evaluation of mathematical models to answer questions about the relevance of these factors in the development and progression of glaucoma.

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He pointed out that numerous studies have suggested that low diastolic perfusion pressure is an important risk factor for the prevalence of glaucoma, beginning with the Baltimore study up to the recent South India study. Some, such as the Barbados Eye study and the Rotterdam study, have suggested that perfusion pressure is a risk factor for the glaucoma incidence and progression. While other studies, such as the Early Manifest Glaucoma study, have suggested that the perfusion pressure is an important factor in glaucoma progression.

Next: More clinicaly relevant?

The Thessalonika study, in which Dr. Harris is an investigator, evaluated progression models for diastolic blood pressure as a continuous variable, and determined that low diastolic blood pressure and anti-hypertensive treatment are independently associated with the structure of the optic disc, he explained.

However, they rethought their approach because of misinterpretations of the original data.

More clinicaly relevant?

“When we analyzed the data and stratified it by the level of blood pressure and treatment, we found that only in subjects with low diastolic blood pressure and treated with anti-hypertensive drugs that structure was associated with ocular perfusion pressure,” he said.

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In the Thessalonika study, they hypothesized that the status of the perfusion pressure-that is, ocular perfusion pressure with or without anti-hypertensive treatment-may be more related to the pathogenesis of glaucoma than the ocular perfusion pressure by itself.

“After subgroup analysis based on the status of the ocular perfusion pressure, we found that diastolic perfusion pressure was significantly associated with glaucoma in those treated with anti-hypertensive medications, and this was not the case in patients not treated with anti-hypertensive drugs,” Dr. Harris reported.

This suggested that the perfusion pressure status may be more clinically relevant than just the level of the perfusion pressure. The findings were published in the American Journal of Ophthalmology (2013;155:843-51. doi: 10.1016/j.ajo.2012.12.007. Epub 2013 Feb 6).

One explanation for this finding is related to the treated patients having more decreases in nocturnal blood pressure with consequent variations in the perfusion pressure. A second explanation is that the anti-hypertensive drugs may disrupt the ability of the blood vessels to autoregulate.

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When conducting research in this area, he noted, it is difficult to isolate all factors that affect perfusion pressure and isolate their effect on the system. 

“There are anatomic and physiologic variations among species and among individual patients,” Dr. Harris said.

Next: Diving into the mathematical model

The mathematical model

This has led to the exploration of mathematical models.

“Basically, this model calculates stresses and strains in the lamina cribosa, which becomes deformed based on the action of the IOP and the retrolaminar pressure,” he said. “We look at fluid/structure interactions. The model describes the relationship between stresses and strains in the lamina cribosa and the blood flow in the vessels.”

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Professors Harris and Giovanna Guidoboni of the Department of Mathematics at IUPUI are collaborators on the dynamic model, Dr. Harris added.

Importantly, this model also considers blood pressure and it simulates a relationship between an increase in IOP and venous collapse, i.e., the Starling resistor effect. A final factor evaluated is autoregulation, which, Dr. Harris said, can turn on, off, or keep constant.

He demonstrated an example of how this model works to interpret clinical data. In this example, three theoretical patients had three different blood pressure levels, low, high, and normal. Among the three patients, the IOPs were changed in the model from 15 mmHg up to 45 mmHg in correspondence with a mean arterial pressure and IOP level. With this information, the model predicts blood flow, of which perfusion pressure is a surrogate.  

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“We saw that at an IOP of less than 26 mmHg, the blood flow plateaus for high blood pressure and normal blood pressure,” he explained. “There is no plateau in a patient with low blood pressure. At IOPs of 26 to 36 mmHg, the same decreasing slope is seen for all three patients.

“Over 36 mmHg, a steeper slope is seen due to what we think is partial venous collapse, which begins earlier in patients with lower blood pressure,” he added.

Next: Concluding thoughts

Conclusions

The data, Dr. Harris noted, corresponds to some of the data from the previously mentioned population-based studies, and offers an explanation of those data.

 “Patients with low blood pressure that lack the ability to autoregulate have lower blood flow levels at any given level of IOP, and, we believe, may have early venous collapse,” he said. “We concluded that high IOP values are likely to be the dominant factor in ocular perfusion pressure causing inadequate or dysfunctional autoregulation.”

He summarized that previous studies are consistent on the finding that low perfusion pressure is a risk factor for glaucoma.

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In theory, ocular perfusion pressure can be incorporated into glaucoma management as a risk factor or a treatment target. However, based on our current knowledge, we must first improve our understanding of the role of perfusion pressure in glaucoma. The complexity of perfusion pressure in and of itself and its interaction with potential risk factors for glaucoma still need to be determined.

Synergy between math models and clinical studies can help weigh the contributions of different factors and mechanisms that influence autoregulation of blood flow in the eye and in the clinical interpretation of data. He said he believes that this understanding may lead in the future to patient-specific evaluations elucidating the complex relationship between IOP, blood pressure, cerebrospinal fluid pressure, and optic nerve blood flow.

Alon Harris, MS, PhD

E: alharris@indiana.edu

Dr. Harris has no financial interest in any aspect of this report.