Peripheral microvascular dysfunction is also present in patients with ischemia and no obstructive coronary artery disease (INOCA)

BACKGROUND: In patients with ischemia and no obstructive coronary artery disease (INOCA), coronary microvascular dysfunction is associated with higher rate of major adverse cardiovascular events. OBJECTIVE: To demonstrate if microvascular dysfunction present in coronary microcirculation of patients with INOCA may be detected noninvasively in their peripheral circulation. METHODS: 25 patients with INOCA and 25 apparently healthy individuals (controls) were subjected to nailfold videocapillaroscopy (NVC) and venous occlusion plethysmography (VOP) to evaluate peripheral microvascular function and blood collection for biomarkers analysis, including soluble vascular cell adhesion molecule-1 (sVCAM-1), endothelin-1 (ET-1) and C-reactive protein (CRP). RESULTS: Red blood cell velocity (RBCV) before and after ischemia (RBCVmax) were significantly lower in patients with INOCA (p = 0.0001). Time to reach maximal red blood cell velocity (TRBCVmax) was significantly longer in INOCA group (p = 0.0004). Concerning VOP, maximal blood flow (p = 0.004) and its relative increment were significantly lower in patients with INOCA (p = 0.0004). RBCVmax showed significant correlations with sVCAM-1 (r = –0.38, p < 0.05), ET-1 (r = –0.73, p < 0.05) and CRP (r = –0.33, p < 0.05). Relative increment of maximal post-ischemic blood flow was significantly correlated with sVCAM-1 (r = –0.42, p < 0.05) and ET-1 (r = –0.48, p < 0.05). CONCLUSIONS: The impairment of microvascular function present in coronary microcirculation of patients with INOCA can be also detected in peripheral microcirculation.

Frequency selective neuronal modulation triggers spreading depolarizations in the rat endothelin-1 model of stroke

Ischemia is one of the most common causes of acquired brain injury. Central to its noxious sequelae are spreading depolarizations (SDs), waves of persistent depolarizations which start at the location of the flow obstruction and expand outwards leading to excitotoxic damage. The majority of acute stage of stroke studies to date have focused on the phenomenology of SDs and their association with brain damage. In the current work, we investigated the role of peri-injection zone pyramidal neurons in triggering SDs by optogenetic stimulation in an endothelin-1 rat model of focal ischemia. Our concurrent two photon fluorescence microscopy data and local field potential recordings indicated that a ≥ 60% drop in cortical arteriolar red blood cell velocity was associated with SDs at the ET-1 injection site. SDs were also observed in the peri-injection zone, which subsequently exhibited elevated neuronal activity in the low-frequency bands. Critically, SDs were triggered by low- but not high-frequency optogenetic stimulation of peri-injection zone pyramidal neurons. Our findings depict a complex etiology of SDs post focal ischemia and reveal that effects of neuronal modulation exhibit spectral and spatial selectivity.

Metabolic Changes Induced by High-Fat Meal Evoke Different Microvascular Responses in Accordance with Adiposity Status

Background. Frequently, ingestion of lipids exceeds our daily requirements and constantly exposes humans to circulating lipid overload which may lead to endothelial dysfunction (ED), the earliest marker of atherosclerosis. Nailfold videocapillaroscopy (NVC) technique can detect ED on microcirculation. Using NVC, we aimed to demonstrate if metabolic alterations evoked by high-fat meals can act differently on microvascular endothelial reactivity in lean and women with obesity.Methods.Women, aged between 19 and 40 years, were allocated to control group (CG) and with obesity group (OBG) and were subjected to blood analysis for determination of glucose, total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) and NVC evaluation at fasting and 30, 60, 120, and 180-min after high-fat meal ingestion. NVC technique evaluated microvascular reactivity through the following variables: red blood cell velocity (RBCV) at rest and after 1-min ischemia (maximal red blood cell velocity,RBCVmax) and time taken to reach it (TRBCVmax). APvalue ≤0.05 was considered significant.Results.High-fat meal promoted a two-phase response in both groups: one until 60-min, associated with glucose and insulin levels, and the other after 120-min, associated with TG levels. Significant differences between groups were observed concerning insulin and HDL-c concentrations only at fasting and TC, TG, and LDL-c levels in all-time points. Regarding microvascular reactivity, RBCV,RBCVmax, andTRBCVmaxwere significantly different in OBG at 30-min compared to baseline.RBCVmaxandTRBCVmaxwere significantly different in CG at 30-min and 60-min comparing to fasting. In all-time points, OBG presented RBCV,RBCVmax , and TRBCVmaxsignificantly different in comparison to CG.Conclusion.High-fat meal worsened ED on microcirculation in women with obesity and induced impairment of endothelial function in lean ones, reinforcing the association between high-fat meal and atherosclerosis.

Intravital imaging of the kidney in a rat model of salt-sensitive hypertension

Hypertension is one of the most prevalent diseases worldwide and a major risk factor for renal failure and cardiovascular disease. The role of albuminuria, a common feature of hypertension and robust predictor of cardiorenal disorders, remains incompletely understood. The goal of this study was to investigate the mechanisms leading to albuminuria in the kidney of a rat model of hypertension, the Dahl salt-sensitive (SS) rat. To determine the relative contributions of the glomerulus and proximal tubule (PT) to albuminuria, we applied intravital two-photon-based imaging to investigate the complex renal physiological changes that occur during salt-induced hypertension. Following a high-salt diet, SS rats exhibited elevated blood pressure, increased glomerular sieving of albumin (GSCalb = 0.0686), relative permeability to albumin (+Δ16%), and impaired volume hemodynamics (−Δ14%). Serum albumin but not serum globulins or creatinine concentration was decreased (−0.54 g/dl), which was concomitant with increased filtration of albumin (3.7 vs. 0.8 g/day normal diet). Pathologically, hypertensive animals had significant tubular damage, as indicated by increased prevalence of granular casts, expansion and necrosis of PT epithelial cells (+Δ2.20 score/image), progressive augmentation of red blood cell velocity (+Δ269 µm/s) and micro vessel diameter (+Δ4.3 µm), and increased vascular injury (+Δ0.61 leakage/image). Therefore, development of salt-induced hypertension can be triggered by fast and progressive pathogenic remodeling of PT epithelia, which can be associated with changes in albumin handling. Collectively, these results indicate that both the glomerulus and the PT contribute to albuminuria, and dual treatment of glomerular filtration and albumin reabsorption may represent an effective treatment of salt-sensitive hypertension.

Plasma syndecan-1 and heparan sulfate correlate with microvascular glycocalyx degradation in hemorrhaged rats after different resuscitation fluids

The endothelial glycocalyx plays an essential role in many physiological functions and is damaged after hemorrhage. Fluid resuscitation may further change the glycocalyx after an initial hemorrhage-induced degradation. Plasma levels of syndecan-1 and heparan sulfate have been used as indirect markers for glycocalyx degradation, but the extent to which these measures are representative of the events in the microcirculation is unknown. Using hemorrhage and a wide range of resuscitation fluids, we studied quantitatively the relationship between plasma biomarkers and changes in microvascular parameters, including glycocalyx thickness. Rats were bled 40% of total blood volume and resuscitated with seven different fluids (fresh whole blood, blood products, and crystalloids). Intravital microscopy was used to estimate glycocalyx thickness in >270 postcapillary venules from 58 cremaster preparations in 9 animal groups; other microvascular parameters were measured using noninvasive techniques. Systemic physiological parameters and blood chemistry were simultaneously collected. Changes in glycocalyx thickness were negatively correlated with changes in plasma levels of syndecan-1 ( r = −0.937) and heparan sulfate ( r = −0.864). Changes in microvascular permeability were positively correlated with changes in both plasma biomarkers ( r = 0.8, P < 0.05). Syndecan-1 and heparan sulfate were also positively correlated ( r = 0.7, P < 0.05). Except for diameter and permeability, changes in local microcirculatory parameters (red blood cell velocity, blood flow, and wall shear rate) did not correlate with plasma biomarkers or glycocalyx thickness changes. This work provides a quantitative framework supporting plasma syndecan-1 and heparan sulfate as valuable clinical biomarkers of glycocalyx shedding that may be useful in guiding resuscitation strategies following hemorrhage.