The Impact of COVID-19 Infection on Macular Capillary Perfusion

Purpose: To evaluate the impact of a prior non-severe COVID-19 infection on retinal microcirculation with optical coherence tomography angiography (OCTA).Methods:A total of 83 eyes of 43 patients with a history of non-severe COVID-19 infection confirmed with a positive PCR test (Group 1) and 30 age-matched healthy controls (Group 2) underwent detailed eye examination including Spectral-Domain OCT (Topcon-Triton Swept Source) and OCTA (RTVue-XR Avanti) scanning. OCTA images (6x6mm) images were used to assess vessel densities (VD) in superficial capillary plexus (SCP) and deep capillary plexus (DCP) and foveal avascular zone (FAZ). Results:The mean duration between the COVID-19 positive PCR test and ocular examination was 144.6±82.2 days (range: 30-270). VD of SCP and DCP in the foveal and perifoveal regions were significantly lower in Group 1 compared to Group 2 (p<0.05). Conclusion:Non-severe COVID-19 infection may cause a decrease in VD of retinal SCP and DCP.

The Effects of Angiotensin II or Angiotensin 1-7 on Rat Pial Microcirculation during Hypoperfusion and Reperfusion Injury: Role of Redox Stress

Renin–angiotensin systems produce angiotensin II (Ang II) and angiotensin 1-7 (Ang 1-7), which are able to induce opposite effects on circulation. This study in vivo assessed the effects induced by Ang II or Ang 1-7 on rat pial microcirculation during hypoperfusion–reperfusion, clarifying the mechanisms causing the imbalance between Ang II and Ang 1-7. The fluorescence microscopy was used to quantify the microvascular parameters. Hypoperfusion and reperfusion caused vasoconstriction, disruption of blood–brain barrier, reduction of capillary perfusion and an increase in reactive oxygen species production. Rats treated with Ang II showed exacerbated microvascular damage with stronger vasoconstriction compared to hypoperfused rats, a further increase in leakage, higher decrease in capillary perfusion and marker oxidative stress. Candesartan cilexetil (specific Ang II type 1 receptor (AT1R) antagonist) administration prior to Ang II prevented the effects induced by Ang II, blunting the hypoperfusion–reperfusion injury. Ang 1-7 or ACE2 activator administration, preserved the pial microcirculation from hypoperfusion–reperfusion damage. These effects of Ang 1-7 were blunted by a Mas (Mas oncogene-encoded protein) receptor antagonist, while Ang II type 2 receptor antagonists did not affect Ang 1-7-induced changes. In conclusion, Ang II and Ang 1-7 triggered different mechanisms through AT1R or MAS receptors able to affect cerebral microvascular injury.

Utility of intestinal intravital microscopy for the study of CNS injury-induced immunodepression syndrome (CIDS)

BACKGROUND: Stroke, traumatic brain injury, or other forms of central nervous system (CNS) injury initiate a local inflammatory response. Compensatory anti-inflammatory pathways are activated to limit secondary damage due to inflammation. The associated release of immunosuppressing neuromodulators can result in system-wide immune dysregulation (CNS injury-induced immune-depression syndrome –CIDS). OBJECTIVE: To establish an experimental stroke model where CIDS can be studied by intravital microscopy (IVM). METHODS: We used the photothrombotic stroke (PTS) model in C57BL/6 mice and studied its effects on peripheral immunity following challenge with lipopolysaccharide (LPS). Leukocyte activation, as well as capillary perfusion of the microcirculation, were assessed using intestinal intravital microscopy (IVM). RESULTS: PTS caused a significant reduction in the number of adhering leukocytes in submucosal venules of the terminal ileum of mice challenged with LPS compared to LPS-challenged animals without stroke. Leukocyte rolling was also impacted by PTS in the submucosal venules. Following stroke, we also observed decreased mucosal functional capillary density (FCD). CONCLUSIONS: Our results suggest that PTS with subsequent LPS challenge poses as a viable model to further study CIDS using intravital microscopy of the intestinal microcirculation.

Optical coherence tomographic angiography study of perfusion recovery after surgical lowering of intraocular pressure

We investigated the time and location of retinal perfusion recovery after surgical intraocular pressure (IOP) lowering in glaucoma by using optical coherent tomography angiography (OCTA). Seventeen patients were analyzed. The 4.5 × 4.5-mm OCTA scans centered on the disc were performed preoperatively and postoperatively at 6 weeks, 3 months, and 6 months. The peripapillary retinal nerve fiber layer (NFL) thickness, NFL plexus capillary density (NFLP-CD) and visual field (VF) were measured overall and in 8 corresponding sectors. The low-perfusion area (LPA) was used to assess the cumulative area where local NFLP-CD was significantly below normal. At 6 months, the average IOP decreased 5.3 mmHg (P = 0.004), LPA decreased by 15% (P = 0.005), and NFLP-CD improved by 12% (P < 0.001). The NFL thickness and VF mean deviation didn’t change significantly at any time point. Among the sectors with significant preoperative NFLP-CD loss, the recovery at 6 months was greatest in sectors with minimal preoperative NFL thinning (P < 0.001). In conclusion, surgical IOP lowering may improve NFLP capillary perfusion after 6 months. The perfusion recovery tended to occur in areas with minimal NFL thinning at baseline. OCTA parameters may have potential usefulness as pharmacodynamic biomarkers for glaucoma therapy.

Investigating the relationship between multi-scale perfusion and white matter microstructural integrity in patients with relapsing-remitting MS

Background Multiple sclerosis is characterized by the formation of central nervous system demyelinating lesions with microvasculature inflammation. Objective Evaluate how lesion cerebral perfusion relates to white matter microstructural integrity in patients with RRMS using perfusion MRI and myelin-related T1-weighted to T2-weighted (T1w/T2w) ratios. Methods Forty-eight patients with RRMS were imaged with dynamic susceptibility contrast imaging using SAGE (spin- and gradient-echo) to calculate global and capillary-sized perfusion parameters, including cerebral blood flow (CBF), volume (CBV), and mean transit time (MTT). T1w/T2w ratios were used to indirectly assess white matter microstructural integrity. Results For global perfusion metrics, CBF was reduced 28.4% in lesion regions of interest (ROIs) compared to normal appearing white matter (NAWM), CBV was reduced 25.9% in lesion ROIs compared to NAWM, and MTT increased 12.9%. For capillary perfusion metrics (via spin-echo (SE)), CBF-SE was reduced 35.7% in lesion ROIs compared to NAWM, CBV-SE was reduced 35.2% in lesion ROIs compared to NAWM, and MTT-SE increased 9.1%. Capillary-level CBF was correlated (ρ = 0.34, p = 0.024) with white matter microstructural integrity in lesion ROIs. Conclusion This study demonstrates that lesion perfusion is reduced at both the global and capillary level and capillary-associated hypoperfusion is associated with reduced white matter microstructural integrity in RRMS.

Hypoxic Exercise Training Elevates Erythrocyte Aggregation

Pathological erythrocyte aggregation reduces capillary perfusion and oxygen transfer to tissue, which is determined by the negative surface charge on the erythrocyte membrane (intrinsic aggregability) and fibrinogen–erythrocyte interaction (extrinsic factor). Exercise-induced oxidative stress is important for rheological adaptation to training but may also cause erythrocyte senescence. This study clarifies the effects of hypoxic exercise training on intrinsic/extrinsic factors of aggregation. In total, 60 healthy sedentary males were randomly assigned to either hypoxic (HE; FIO2 = 0.15) or normoxic exercise training (NE; FIO2 = 0.21) groups for 30 min·d−1, 5 d·wk−1 for 6 weeks at 60 % of the maximum work rate or to a control group (CTL). A hypoxia exercise test (HET, FIO2 = 0.12) was performed before and after the intervention. Erythrocyte aggregation was assessed by ektacytometry, and fibrinogen binding affinity and senescence biomarkers were assessed by flow cytometry. An acute 12% oxygen HET significantly enhanced erythrocyte global aggregation through intrinsic aggregability. Resting aggregation is promoted by both intrinsic aggregability and fibrinogen binding probability and force after HE, whereas NE is mainly associated with ameliorated fibrinogen–erythrocyte interactions. The HET still facilitated global aggregation after HE because of the augmented fibrinogen-related factors, even though the intrinsic factor was suppressed. Additionally, HE further increased reticulocyte counts while reducing the expression of CD47 and CD147. Resting aggregability is promoted by both intrinsic and extrinsic factors after HE, whereas NE is mainly associated with an ameliorated affinity for fibrinogen. Although an accelerated turnover rate was observed, HE further led to erythrocyte senescence.

Precapillary sphincters and pericytes at first-order capillaries as key regulators for brain capillary perfusion

Rises in local neural activity trigger local increases of cerebral blood flow, which is essential to match local energy demands. However, the specific location of microvascular flow control is incompletely understood. Here, we used two-photon microscopy to observe brain microvasculature in vivo. Small spatial movement of a three-dimensional (3D) vasculature makes it challenging to precisely measure vessel diameter at a single x–y plane. To overcome this problem, we carried out four-dimensional (x–y–z–t) imaging of brain microvessels during exposure to vasoactive molecules in order to constrain the impact of brain movements on the recordings. We demonstrate that rises in synaptic activity, acetylcholine, nitric oxide, cyclic guanosine monophosphate, ATP-sensitive potassium channels, and endothelin-1 exert far greater effects on brain precapillary sphincters and first-order capillaries than on penetrating arterioles or downstream capillaries, but with similar kinetics. The high level of responsiveness at precapillary sphincters and first-order capillaries was matched by a higher level of α-smooth muscle actin in pericytes as compared to penetrating arterioles and downstream capillaries. Mathematical modeling based on 3D vasculature reconstruction showed that precapillary sphincters predominantly regulate capillary blood flow and pressure as compared to penetrating arterioles and downstream capillaries. Our results confirm a key role for precapillary sphincters and pericytes on first-order capillaries as sensors and effectors of endothelium- or brain-derived vascular signals.

Different issue types have different signal intensity on b=0 images and its implication on intravoxel incoherent motion (IVIM) analysis: examples of liver MRI

Intravoxel incoherent motion (IVIM) theory in MRI was proposed to account for the effect of vessel/capillary perfusion on the aggregate diffusion weighted MR signal. The prevalent IVIM modeling is based on equation-1: SI(b)/SI(0) = (1 -PF) × exp(-b × Dslow) + PF × exp(-b × Dfast) [1] where SI(b) and SI(0) denote the signal intensity of images acquired with the b-factor value of b and b=0 s/mm2, respectively. We recently reported that, for the liver and likely for other organs as well, IVIM modeling of the perfusion component is constrained by the diffusion component, with a reduced Dslow measure leading to artificially higher PF and Dfast measures. With higher b-value associated lower image signal of the targeted tissue, Euqation-1 is focused on describing the signal decay pattern along increasingly higher b-values by three IVIM parameters. Signal intensity at each b-value (i.e., SI(b)) is normalised by the signal intensity of b=0 image (i.e., SI(0)). We noted an apparent problem for Euqation-1. For example, if we want to compare the IVIM parameters of the normal liver parenchyma and a liver tumor, following Euqation-1 we will take the assumption that the SI(0) of the normal parenchyma and the tumor are the same and considered equally as 1 (or 100) for the biexponential decay modelling. However, this assumption is invalid for many scenarios. From our liver IVIM database of 27 healthy female subjects, we chose six of the youngest subjects (20-27 yrs) and six of the oldest subjects (58-71 yrs) and measured the signals of the liver and left erector spinae muscle on b=0 and 2 s/mm2 images. The results show, while there was no apparent difference of left erector spinae muscle signal among the young and elderly groups, the elderly group’s liver SI(0) is approximately 20 % lower than that of young group. This difference skewed the ratios of various SI(b)/SI(0) and the followed IVIM parameter determination. The general trend is that lower liver SI(0) is associated with lower Dslow and higher PF and Dfast. If IVIM bi-exponential decay fitting starts from a very low non-zero b images (such as b=2 s/mm2 images), this problem persists. We performed an additional analysis of our IVIM database of five cirrhotic livers and the results show SI(b=2) of cirrhotic right liver is positively associated Dslow (Pearson r=0.687), and negatively associated with PF (Pearson r=-0.733). Though the examples we used in this letter are on liver aging and liver fibrosis, the points discussed are expected to be generalisable to other pathologies and to other organs.