On the Indeterminates of Glaucoma:the Controversy of Arterial Blood Pressure and Retinal Perfusion

Glaucoma is a chronic eye disease characterized by thinning of the retina, death of ganglion cells, and progressive loss of vision, eventually leading to blindness. The prevalence of glaucoma is estimated at 1-3% of those over 40 years old. With a constantly aging population, this number is expected to increase significantly over the next 10 years. Even with treatment, about 15% of people with glaucoma currently develop residual vision or tunnel vision and eventually become blind or partially sighted. The mechanisms behind ganglion cell death are poorly understood. Elevated eye pressure is the main risk factor for glaucoma, but treatment in the form of medication, laser, or surgery can only slow the decline, not stop it. In addition, high intraocular pressure is neither necessary nor sufficient for the development of glaucoma, indicating the existence of other unknown risk factors. It has been established that the death of ganglion cells results in a decreased oxygen demand and a concomitant decrease in blood flow. However, there is also a hypothesis that reduced or unstable blood supply is not only a consequence, but also a cause of glaucoma. This is known as the ‘chicken-egg’ dilemma in glaucoma. It is supported by the observation that the risk of developing glaucoma is higher in people with very low blood pressure (sometimes even as a result of overtreatment of high blood pressure).This dissertation is an attempt to methodically examine whether blood pressure can be linked to changes in the retina that could suggest susceptibility to glaucoma. For this purpose, we analyze epidemiological data from the Groningen Longitudinal Glaucoma Study, we use advanced imaging techniques to model the microcirculation, and we describe its relationship with the neural structure and oxygen consumption of the retina. We provide evidence leaning towards the existence of a vascular component, likely pertinent to glaucoma

Retinal Oxygen Delivery and Extraction in Ophthalmologically Healthy Subjects With Different Blood Pressure Status

PURPOSE: To compare retinal oxygen delivery (DO(2)) and oxygen extraction (VO(2)) in ophthalmologically healthy subjects with different blood pressure (BP) status. METHODS: In this case-control study, we prospectively included 93 eyes of 93 subjects (aged 50–65 years) from a Dutch cohort (n = 167,000) and allocated them to four groups (low BP, normal BP [controls], treated arterial hypertension [AHT], untreated AHT). We estimated vascular calibers from fundus images and fractal dimension from optical coherence tomography angiography scans. We combined calibers, fractal dimension, BP, and intraocular pressure measurements in a proxy of retinal blood flow (RBF), using a Poiseuille-based model. We measured arterial and venous oxygen saturations (S(a)O(2), S(v)O(2)) with a scanning laser ophthalmoscope. We calculated the DO(2) and VO(2) from the RBF, S(a)O(2), and S(v)O(2). We compared the DO(2) and VO(2) between groups and investigated the DO(2)–VO(2) association. RESULTS: DO(2) and VO(2) were different between groups (P = 0.009, P = 0.036, respectively). In a post hoc analysis, the low BP group had lower DO(2) than the untreated AHT group (P = 4.9 × 10(−4)). The low BP group and the treated AHT group had a lower VO(2) than the untreated AHT group (P = 0.021 and P = 0.034, respectively). There was a significant DO(2)–VO(2) correlation (R(obs) = 0.65, b(obs) = 0.51, P = 2.4 × 10(−12)). After correcting for shared measurement error, the slope was not significant. CONCLUSIONS: The DO(2) and VO(2) were altered in ophthalmologically healthy subjects with different BP status. Future studies could elucidate whether these changes can explain the increased risk of ophthalmic pathologies in those subjects. TRANSLATIONAL RELEVANCE: Understanding the baseline interplay between BP, retinal perfusion, and oxygenation allows for improved evaluation of retinal disease manifestation

U-shaped effect of blood pressure on structural OCT metrics and retinal perfusion in ophthalmologically healthy subjects

PURPOSE: We wanted to investigate the association of blood pressure (BP) status with the ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) thickness of nonglaucomatous eyes and to elucidate whether this effect is related to vascular metrics proxying retinal perfusion. METHODS: For this case-control study, we prospectively included 96 eyes of 96 healthy subjects (age 50–65) from a large-scale population-based cohort in the northern Netherlands (n = 167,000) and allocated them to four groups (low BP, normal BP [controls], treated arterial hypertension [AHT], untreated AHT). We measured macular GCIPL and RNFL (mRNFL) and peripapillary RNFL (pRNFL) thicknesses with optical coherence tomography (OCT). We estimated retinal blood flow (RBF), retinal vascular resistance (RVR), and autoregulatory reserve (AR) from quantitative OCT-angiography, fundus imaging, BP, and intraocular pressure. We compared structural and vascular metrics across groups and performed mediation analysis. RESULTS: Compared to controls, GCIPL was thinner in the low BP group (P = 0.013), treated hypertensives (P = 0.007), and untreated hypertensives (P = 0.007). Treated hypertensives exhibited the thinnest mRNFL (P = 0.001), temporal pRNFL (P = 0.045), and inferior pRNFL (P = 0.034). The association of GCIPL thickness with BP was mediated by RBF within the combined low BP group and controls (P = 0.003), by RVR and AR within the combined treated hypertensives and controls (P = 0.001, P = 0.032), and by RVR within the combined untreated antihypertensives and controls (P = 0.022). CONCLUSIONS: Inner retinal thinning was associated with both tails of the BP distribution and with ineffective autoregulation. Longitudinal studies could clarify whether these defects can explain the reported glaucomatous predisposition of these population groups

Microcirculatory model predicts blood flow and autoregulation range in the human retina:in vivo investigation with laser speckle flowgraphy

In this study, we mathematically predict retinal vascular resistance (RVR) and retinal blood flow (RBF), we test predictions using laser speckle flowgraphy (LSFG), we estimate the range of vascular autoregulation, and we examine the relationship of RBF with the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC). Fundus, optical coherence tomography (OCT), and OCT-angiography images, systolic/diastolic blood pressure (SBP/DBP), and intraocular pressure (IOP) measurements were obtained float 36 human subjects. We modeled two circulation markers (RVR and RBF) and estimated individualized lower/higher autoregula tion limits (LARL/HARL), using retinal vessel calibers, fractal dimen- sion, perfusion pressure, and population-based hematocrit values. Quantitative LSFG waveforms were extracted from vessels of the same eyes, before and during IOP elevation. LSFG metrics explained most variance in RVR (R-2 =0.77/P = 6.9.10(-9)) and RBF (R-2 =0.65/P = 1.0.10(-6)), suggesting that the markers strongly reflect blood flow physiology. Higher RBF was associated with thicker RNFL (P = 4.0.10(-4)) and GCC (P = 0.003), thus also verifying agreement with structural measurements. LARL was at SBP/DBP of 105/65 mmHg for the average subject without arterial hypertension and at 115/75 mmHg for the average hypertensive subject. Moreover, during IOP elevation, changes in RBF were more pronounced than changes in RVR. These observations physiologically imply that healthy subjects are already close to LARL, thus prone to hypoperfusion. In conclusion, we modeled two clinical markers and described a novel method to predict individualized autoregulation limits. These findings could improve understanding of retinal perfusion and pave the way for personalized intervention decisions, when treating patients with coexisting ophthalmic and cardiovascular pathologies. NEW & NOTEWORTHY We describe and test a new approach to quantify retinal blood flow, based on standard clinical examinations and imaging techniques, linked together with a physiological model. We use these findings to generate individualized estimates of the autoregulation range. We provide evidence that healthy subjects are closer to the lower autoregulation limit than thought before. This suggests that some retinas are less prepared to withstand hypoperfusion, even after small intraocular pressure rises or blood pressure drops

Association of Systemic Medication Exposure With Glaucoma Progression and Glaucoma Suspect Conversion in the Groningen Longitudinal Glaucoma Study

PURPOSE. To determine the association of statins, five classes of antihypertensive medications, and proton pump inhibitors with (1) primary open-angle glaucoma (POAG) progression and (2) conversion of POAG suspects to POAG. METHODS. We retrospectively investigated the records of a cohort with POAG cases and suspects from the Groningen Longitudinal Glaucoma Study. To quantify visual field (VF) deterioration in cases, we used the rate of progression of the mean deviation (MD). Suspects were considered to have converted at the time point after which two consecutive VF tests for at least one eye were abnormal (glaucoma hernifield test outside normal limits). Progression and conversion were analyzed with quantile and logistic regression, respectively, with the systemic medications as predictors, controlling for age, sex, body mass index, pretreatment IOP, corneal thickness, and baseline MD. The multivariable models were built with and without IOP intervention. RESULTS. No systemic medications were associated with POAG progression in the final IOP/treatment-adjusted or unadjusted model. However, angiotensin II receptor blockers (ARBs) appeared to slow progression in older patients (b = 0.014, P = 0.0001). Angiotensin-converting enzyme inhibitors (ACM) were significantly associated with a decrease in POAG suspect conversion in both the IOP/treatment-adjusted and -unadjusted model (odds ratio [OR] 0.23, 95% confidence interval [CI] 0.07-0.79, P = 0.012; OR=0.24, 95% CI 0.07-0.78, P = 0.021, respectively), as were ARBs (OR 0.12, 95% CI 0.01-0.98, P = 0.014; OR 0.11, 95% CI 0.01-0.87, P = 0.005, respectively). CONCLUSIONS. No overall association of VF progression with systemic medication was found; ARBs delayed progression in older patients. ACEIs and ARBs were associated with lower risk of suspect conversion. The pathophysiology of this relationship is to be disentangled

Combined multi-modal assessment of glaucomatous damage with electroretinography and optical coherence tomography/angiography

Purpose: To compare the diagnostic performance and to evaluate the interrelationship of electroretinographical and structural and vascular measures in glaucoma. Methods: For 14 eyes of 14 healthy controls and 15 eyes of 12 patients with glaucoma ranging from preperimetric to advanced stages optical coherence tomog-raphy (OCT), OCT-angiography (OCT-A), and electrophysiological measures (multifocal photopic negative response ratio [mfPhNR] and steady-state pattern electroretinogra-phy [ssPERG]) were applied to assess changes in retinal structure, microvasculature, and function, respectively. The diagnostic performance was assessed via area-under-curve (AUC) measures obtained from receiver operating characteristics analyses. The interre-lation of the different measures was assessed with correlation analyses. Results: The mfPhNR, ssPERG amplitude, parafoveal (pfVD) and peripapillary vessel density (pVD), macular ganglion cell inner plexiform layer thickness (mGCIPL) and peripapillary retinal nerve fiber layer thickness (pRNFL) were significantly reduced in glaucoma. The AUC for mfPhNR was highest among diagnostic modalities (AUC: 0.88, 95% confidence interval: 0.75–1.0, P < 0.001), albeit not statistically different from that for macular (mGCIPL: 0.76, 0.58–0.94, P < 0.05; pfVD: 0.81, 0.65–0.97, P < 0.01) or peripapillary imaging (pRNFL: 0.85, 0.70–1.0, P < 0.01; pVD: 0.82, 0.68–0.97, P < 0.01). Combined functional/vascular measures yielded the highest AUC (mfPhNR-pfVD: 0.94, 0.85–1.0, P < 0.001). The functional/structural measure correlation (mfPhNR-mGCIPL correlation coefficient [rs ]: 0.58, P = 0.001; mfPhNR-pRNFL rs: 0.66, P < 0.001) was stronger than the functional-vascular correlation (mfPhNR-pfVD rs: 0.29, P = 0.13; mfPhNR-pVD rs: 0.54, P = 0.003). Conclusions: The combination of ERG measures and OCT-A improved diagnostic performance and enhanced understanding of pathophysiology in glaucoma. Translational Relevance: Multimodal assessment of glaucoma damage improves diagnostics and monitoring of disease progression

Imaging of Left Main Coronary Artery; Untangling the Gordian Knot

Left Main Coronary Artery (LMCA) disease is considered a standout manifestation of coronary artery disease (CAD), because it is accompanied by the highest mortality. Increased mortality is expected, because LMCA is responsible for supplying up to 80% of total blood flow to the left ventricle in a right-dominant coronary system. Due to the significant progress of biomedical technology, the modern drug-eluting stents have remarkably improved the prognosis of patients with LMCA disease treated invasively. In fact, numerous randomized trials provided similar results in one- and five-year survival of patients treated with percutaneous coronary interventions (PCI) -guided with optimal imaging and coronary artery bypass surgery (CABG). However, interventional treatment requires optimal imaging of the LMCA disease, such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The aim of this manuscript is to review the main pathophysiological characteristics, to present the imaging techniques of LMCA, and, last, to discuss the future directions in the depiction of LMCA disease.</p

Quantification and Repeatability of Vessel Density and Flux as Assessed by Optical Coherence Tomography Angiography

Purpose: To determine the intrasession repeatability (test-retest variability) of parafoveal and peripapillary perfused capillary density (PCD) and normalized flux index (NFI) as assessed with Canon OCT-HS100 angiography. Methods: Pairs of optical coherence tomography angiography (OCT-A) images were obtained from the parafoveal and peripapillary region of 30 eyes of 30 healthy subjects. PCD and NFI were calculated using generic image-processing software. Macular ganglion-cell complex thickness (GCC) and peripapillary retinal nerve fiber layer thickness (RNFLT) were also recorded. Bland-Altman analysis was performed and the coefficient of repeatability (CoR) and intraclass correlation coefficient (ICC) were calculated. Correlations of parafoveal PCD/NFI with GCC and of peripapillary PCD/NFI with RNFLT were also computed. Results: Mean (standard deviation) parafoveal and peripapillary PCD were 40.0% (1.8%) and 44.5% (1.3%), respectively. Corresponding values for NFI were 151.2 (6.8) and 164.2 (3.9). For PCD, ICC was 0.76 for parafoveal and 0.79 for peripapillary measurements; corresponding CoRs were 2.7% and 1.8%. Corresponding values for NFI were 0.62 and 0.67 for ICC and 13.3 and 7.0 for CoR. Average measures ICC was 0.87/0.88 and 0.76/0.80 for the parafoveal/peripapillary PCD and NFI, respectively. PCD and NFI were weakly correlated with GCC (r = 0.39, P = 0.035; r = 0.33, P = 0.077) and moderately correlated with RNFLT (r = 0.43, P = 0.017; r = 0.55, P = 0.002). Conclusions: Repeatability of a commercially available OCT-A with generic image-processing software was good (NFI) to excellent (PCD). Our results indicate that changes surpassing the variability in healthy subjects should be easily detectable in a clinical setting. Translational Relevance: Repeatability estimates provide information regarding the relevance of changes in retinal perfusion