IOP and OPP Fluctuation as Risk Factors for Glaucoma

 描述（由申请人提供）：在所有主要的前瞻性临床试验中，发现眼内压（IOP）和年龄是青光眼发生和进展的最一致的独立风险因素，尽管在大多数人群中IOP并未随年龄增加而增加。青光眼在非洲血统的人中也更为普遍。降低IOP是唯一的临床治疗，已被证明可以延缓青光眼的发作和进展，但一旦受损，视神经乳头（ONH）被认为更容易进一步发展为青光眼，即使在临床干预已将平均IOP降低到“正常”水平后。我们以前解释这些发现意味着随着年龄的增长，非洲血统和先前的损害，ONH越来越容易受到昏迷性损伤。然而，还有一种似是而非的解释。我们的遥测IOP数据显示，在清醒时间内，眼睛每小时经受约7，000次> 5mmHg的IOP尖峰。此外，高于基线>1 mmHg的IOP峰值是眼睛在清醒时间内平均必须吸收的总IOP损伤的高达15%的原因。这是一个非凡的发现，因为IOP尖峰代表了IOP总损伤的先前未知的和潜在的高度有害的成分，其尚未在先前的动物或临床研究中表征或考虑。 我们假设，除了平均IOP外，更大的IOP和眼灌注压（IOP）波动独立地导致青光眼的发作和进展。我们将通过阐明与年龄和疾病相关的IOP、OPP变化及其波动（与视网膜神经节细胞（RGC）轴突丢失和IOP升高诱导的眼被硬化相关）来测试这一组织假设。 对“波动”假说的支持将导致对IOP和IOP波动在增加的年龄和疾病相关的青光眼易感性中的重要性的全新理解，并为全新的临床诊断和治疗方式提供强有力的理论基础，这些临床诊断和治疗方式通过改变眼被膜硬度或眼内抑制IOP波动来降低IOP和IOP波动。如果我们的结果不支持“波动”假设，我们获得的关于这些变量的自然波动的知识将重新定义患者的适当IOP测量频率并告知患者护理。

 DESCRIPTION (provided by applicant): Intraocular pressure (IOP) and age were found to be the most consistent independent risk factors for development and progression of glaucoma in all of the major prospective clinical trials, even though IOP has not been shown to increase with age in most populations. Glaucoma is also much more prevalent in persons of African ancestry. Lowering IOP is the only clinical treatment that has been shown to retard the onset and progression of glaucoma, but once damaged, the optic nerve head (ONH) is thought to be more susceptible to further glaucomatous progression even after clinical intervention has lowered mean IOP to `normal' levels. We have previously interpreted these findings to mean that the ONH is increasingly vulnerable to glaucomatous injury with advancing age, African ancestry, and prior damage. There is a plausible alternative explanation, however. Our telemetric IOP data show that the eye is subjected to about 7,000 IOP spikes >5 mmHg per hour during waking hours. Also, IOP spikes >1 mmHg above baseline are responsible for up to 15% of the total IOP insult the eye must absorb during waking hours on average. This is an extraordinary finding, in that IOP spikes represent a previously unknown and potentially highly injurious component of the IOP total insult that has yet to be characterized or considered in previous animal or clinical studies. We hypothesize that greater IOP and ocular perfusion pressure (OPP) fluctuation independently contribute to the onset and progression of glaucoma in addition to mean IOP. We will test this organizing hypothesis by elucidating the age- and disease-related changes in IOP, OPP, and their fluctuations as they relate to retinal ganglion cell (RGC) axon loss and elevated IOP-induced ocular coat stiffening. Support for the "fluctuation" hypothesis would lead to an entirely new understanding of the importance of IOP and OPP fluctuation in the increased age- and disease-related susceptibility to glaucoma and provide strong rationale for totally new clinical diagnosis and treatment modalities that employ IOP and OPP fluctuation reduction through modification of ocular coats stiffness or intraocular damping of IOP fluctuations. If our results do not support the "fluctuation" hypothesis, the knowledge we gain about the natural fluctuations of these variables will redefine the appropriate IOP measurement frequency in patients and inform patient care.