PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease.

Neurovascular coupling (NVC), a vital physiological process that rapidly and precisely directs localized blood flow to the most active regions of the brain, is accomplished in part by the vast network of cerebral capillaries acting as a sensory web capable of detecting increases in neuronal activity and orchestrating the dilation of upstream parenchymal arterioles. Here, we report a Col4a1 mutant mouse model of cerebral small vessel disease (cSVD) with age-dependent defects in capillary-to-arteriole dilation, functional hyperemia in the brain, and memory. The fundamental defect in aged mutant animals was the depletion of the minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) in brain capillary endothelial cells, leading to the loss of inwardly rectifying K+ (Kir2.1) channel activity. Blocking phosphatidylinositol-3-kinase (PI3K), an enzyme that diminishes the bioavailability of PIP2 by converting it to phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3), restored Kir2.1 channel activity, capillary-to-arteriole dilation, and functional hyperemia. In longitudinal studies, chronic PI3K inhibition also improved the memory function of aged Col4a1 mutant mice. Our data suggest that PI3K inhibition is a viable therapeutic strategy for treating defective NVC and cognitive impairment associated with cSVD.

High-frequency repetitive transcranial magnetic stimulation promotes ipsilesional functional hyperemia and motor recovery in mice with ischemic stroke.

Neurovascular decoupling plays a significant role in dysfunction following an ischemic stroke. This study aimed to explore the effect of low- and high-frequency repetitive transcranial magnetic stimulation on neurovascular remodeling after ischemic stroke. To achieve this goal, we compared functional hyperemia, cerebral blood flow regulatory factors, and neurochemical transmitters in the peri-infract cortex 21 days after a photothrombotic stroke. Our findings revealed that low- and high-frequency repetitive transcranial magnetic stimulation increased the real-time cerebral blood flow in healthy mice and improved neurobehavioral outcomes after stroke. Furthermore, high-frequency (5-Hz) repetitive transcranial magnetic stimulation revealed stronger functional hyperemia recovery and increased the levels of post-synaptic density 95, neuronal nitric oxide synthase, phosphorylated-endothelial nitric oxide synthase, and vascular endothelial growth factor in the peri-infract cortex compared with low-frequency (1-Hz) repetitive transcranial magnetic stimulation. The magnetic resonance spectroscopy data showed that low- and high-frequency repetitive transcranial magnetic stimulation reduced neuronal injury and maintained excitation/inhibition balance. However, 5-Hz repetitive transcranial magnetic stimulation showed more significant regulation of excitatory and inhibitory neurotransmitters after stroke than 1-Hz repetitive transcranial magnetic stimulation. These results indicated that high-frequency repetitive transcranial magnetic stimulation could more effectively promote neurovascular remodeling after stroke, and specific repetitive transcranial magnetic stimulation frequencies might be used to selectively regulate the neurovascular unit.

Network response of brain microvasculature to neuronal stimulation.

Neurovascular coupling (NVC), or the adjustment of blood flow in response to local increases in neuronal activity is a hallmark of healthy brain function, and the physiological foundation for functional magnetic resonance imaging (fMRI). However, it remains only partly understood due to the high complexity of the structure and function of the cerebrovascular network. Here we set out to understand NVC at the network level, i.e. map cerebrovascular network reactivity to activation of neighbouring neurons within a 500×500×500 µm3 cortical volume (∼30 high-resolution 3-nL fMRI voxels). Using 3D two-photon fluorescence microscopy data, we quantified blood volume and flow changes in the brain vessels in response to spatially targeted optogenetic activation of cortical pyramidal neurons. We registered the vessels in a series of image stacks acquired before and after stimulations and applied a deep learning pipeline to segment the microvascular network from each time frame acquired. We then performed image analysis to extract the microvascular graphs, and graph analysis to identify the branch order of each vessel in the network, enabling the stratification of vessels by their branch order, designating branches 1-3 as precapillary arterioles and branches 4+ as capillaries. Forty-five percent of all vessels showed significant calibre changes; with 85 % of responses being dilations. The largest absolute CBV change was in the capillaries; the smallest, in the venules. Capillary CBV change was also the largest fraction of the total CBV change, but normalized to the baseline volume, arterioles and precapillary arterioles showed the biggest relative CBV change. From linescans along arteriole-venule microvascular paths, we measured red blood cell velocities and hematocrit, allowing for estimation of pressure and local resistance along these paths. While diameter changes following neuronal activation gradually declined along the paths; the pressure drops from arterioles to venules increased despite decreasing resistance: blood flow thus increased more than local resistance decreases would predict. By leveraging functional volumetric imaging and high throughput deep learning-based analysis, our study revealed distinct hemodynamic responses across the vessel types comprising the microvascular network. Our findings underscore the need for large, dense sampling of brain vessels for characterization of neurovascular coupling at the network level in health and disease.

Mapping cutaneous field carcinogenesis of nonmelanoma skin cancer using mesoscopic imaging of pro-inflammation cues.

Nonmelanoma skin cancers remain the most widely diagnosed types of cancers globally. Thus, for optimal patient management, it has become imperative that we focus our efforts on the detection and monitoring of cutaneous field carcinogenesis. The concept of field cancerization (or field carcinogenesis), introduced by Slaughter in 1953 in the context of oral cancer, suggests that invasive cancer may emerge from a molecularly and genetically altered field affecting a substantial area of underlying tissue including the skin. A carcinogenic field alteration, present in precancerous tissue over a relatively large area, is not easily detected by routine visualization. Conventional dermoscopy and microscopy imaging are often limited in assessing the entire carcinogenic landscape. Recent efforts have suggested the use of noninvasive mesoscopic (between microscopic and macroscopic) optical imaging methods that can detect chronic inflammatory features to identify pre-cancerous and cancerous angiogenic changes in tissue microenvironments. This concise review covers major types of mesoscopic optical imaging modalities capable of assessing pro-inflammatory cues by quantifying blood haemoglobin parameters and hemodynamics. Importantly, these imaging modalities demonstrate the ability to detect angiogenesis and inflammation associated with actinically damaged skin. Representative experimental preclinical and human clinical studies using these imaging methods provide biological and clinical relevance to cutaneous field carcinogenesis in altered tissue microenvironments in the apparently normal epidermis and dermis. Overall, mesoscopic optical imaging modalities assessing chronic inflammatory hyperemia can enhance the understanding of cutaneous field carcinogenesis, offer a window of intervention and monitoring for actinic keratoses and nonmelanoma skin cancers and maximise currently available treatment options.

Feasibility of Multiparametric Perfusion Assessment in Diabetic Foot Ulcer Using Intravoxel Incoherent Motion and Blood Oxygenation-Level Dependent MRI.

BACKGROUND: Patients with type-2 diabetes (T2DM) are at increased risk of developing diabetic foot ulcers (DFU) and experiencing impaired wound healing related to underlying microvascular disease. PURPOSE: To evaluate the sensitivity of intra-voxel incoherent motion (IVIM) and blood oxygen level dependent (BOLD) MRI to microvascular changes in patients with DFUs. STUDY TYPE: Case-control. POPULATION: 20 volunteers who were age and body mass index matched, including T2DM patients with DFUs (N = 10, mean age = 57.5 years), T2DM patients with controlled glycemia and without DFUs (DC, N = 5, mean age = 57.4 years) and healthy controls (HC, N = 5, mean age = 52.8 years). FIELD STRENGTH/SEQUENCE: 3T/multi-b-value IVIM and dynamic BOLD. ASSESSMENT: Resting IVIM parameters were obtained using a multi-b-value diffusion-weighted imaging sequence and two IVIM models were fit to obtain diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f) and microvascular volume fraction (MVF) parameters. Microvascular reactivity was evaluated by inducing an ischemic state in the foot with a blood pressure cuff during dynamic BOLD imaging. Perfusion indices were assessed in two regions of the foot: the medial plantar (MP) and lateral plantar (LP) regions. STATISTICAL TESTS: Effect sizes of group mean differences were assessed using Hedge's g adjusted for small sample sizes. RESULTS: DFU participants exhibited elevated D*, f, and MVF values in both regions (g ≥ 1.10) and increased D (g = 1.07) in the MP region compared to DC participants. DC participants showed reduced f and MVF compared to HC participants in the MP region (g ≥ 1.06). Finally, the DFU group showed reduced tolerance for ischemia in the LP region (g = -1.51) and blunted reperfusion response in both regions (g < -2.32) compared to the DC group during the cuff-occlusion challenge. DATA CONCLUSION: The combined use of IVIM and BOLD MRI shows promise in differentiating perfusion abnormalities in the feet of diabetic patients and suggests hyperperfusion in DFU patients. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

The effect of short-term remote ischemic preconditioning on endothelial function of patients with chronic kidney disease: A randomized pilot study.

AIM: Patients with chronic kidney disease (CKD) are more susceptible to endothelial dysfunction and cardiovascular disease (CV). Remote ischemic preconditioning (rIPC) has been proven efficient in improving endothelial function and lowering the risk of CV. However, the safety and effect of rIPC on endothelial function in patients with CKD have not been effectively assessed. METHODS: 45 patients with CKD (average estimated glomerular filtration rate: 48.4 mL/min/1.73 m2) were randomly allocated to either 7-day daily upper-arm rIPC (4 × 5 min 200 mmHg, interspaced by 5-min reperfusion) or control (4 × 5 min 60 mmHg, interspaced by 5-min reperfusion). Vascular endothelial function was assessed by natural log-transformed reactive hyperemia index (LnRHI) before and after a 7-day intervention. Arterial elasticity was assessed by augmentation index (AI). RESULTS: The results showed that LnRHI could be improved by rIPC treatment (Pre = 0.57 ± 0.04 vs. Post = 0.67 ± 0.04, p = .001) with no changes relative to control (Pre = 0.68 ± 0.06 vs. Post = 0.64 ± 0.05, p = .470). Compared with the control group, the improvement of LnRHI was greater after rIPC treatment (rIPC vs. Control: 0.10 ± 0.03 vs. -0.04 ± 0.06, between-group mean difference, -0.15 [95% CI, -0.27 to -0.02], p = .027), while there was no significant difference in the change of AI@75 bpm (p = .312) between the two groups. CONCLUSION: RIPC is safe and well tolerated in patients with CKD. This pilot study suggests that rIPC seems to have the potential therapeutic effect to improve endothelial function. Of note, further larger trials are still warranted to confirm the efficacy of rIPC in improving endothelial function in CKD patients.

Central and peripheral haemodynamics at exercise onset: the role of central command.

PURPOSE: The involvement of central command in central hemodynamic regulation during exercise is relatively well-known, although its contribution to peripheral hemodynamics at the onset of low-intensity contractions is debated. This study sought to examine central and peripheral hemodynamics during electrically-evoked muscle contractions (without central command) and voluntary muscle activity (with central command). METHODS: Cyclic quadriceps isometric contractions (1 every second), either electrically-evoked (ES; 200 ms trains composed of 20 square waves) or performed voluntarily (VC), were executed by 10 healthy males (26 ± 3 years). In both trials, matched for force output, peripheral and central hemodynamics were analysed. RESULTS: At exercise onset, both ES and VC exhibited equal peaks of femoral blood flow (1276 ± 849 vs. 1117 ± 632 ml/min, p > 0.05) and vascular conductance (15 ± 11 vs. 13 ± 7 ml/min/mmHg, p > 0.05), respectively. Similar peaks of heart rate (86 ± 16 bpm vs. 85 ± 16 bpm), stroke volume (100 ± 20 vs. 99 ± 27 ml), cardiac output (8.2 ± 2.5 vs. 8.5 ± 2.1 L/min), and mean arterial pressure (113 ± 13 vs. 113 ± 3 mmHg), were recorded (all, p > 0.05). After ~ 50 s, all the variables drifted to lower values. Collectively, the hemodynamics showed equal responses. CONCLUSION: These results suggest a similar pathway for the initial (first 40 s) increase in central and peripheral hemodynamics. The parallel responses may suggest an initial minimal central command involvement during the onset of low-intensity contractions, likely associated with a neural drive activation delay or threshold.

PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity.

Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia-two comorbidities without specific treatments. Despite the emerging consensus that SVDs are initiated in the endothelium, the early mechanisms remain largely unknown. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) are early manifestations of the underlying pathogenesis. The capillary endothelial cell strong inward-rectifier K+ channel Kir2.1, which senses neuronal activity and initiates a propagating electrical signal that dilates upstream arterioles, is a cornerstone of functional hyperemia. Here, using a genetic SVD mouse model, we show that impaired functional hyperemia is caused by diminished Kir2.1 channel activity. We link Kir2.1 deactivation to depletion of phosphatidylinositol 4,5-bisphosphate (PIP2), a membrane phospholipid essential for Kir2.1 activity. Systemic injection of soluble PIP2 rapidly restored functional hyperemia in SVD mice, suggesting a possible strategy for rescuing functional hyperemia in brain disorders in which blood flow is disturbed.

tPA supplementation preserves neurovascular and cognitive function in Tg2576 mice.

INTRODUCTION: Amyloid beta (Aß) impairs the cerebral blood flow (CBF) increase induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) is required for functional hyperemia, and in mouse models of Aß accumulation tPA deficiency contributes to neurovascular and cognitive impairment. However, it remains unknown if tPA supplementation can rescue Aß-induced neurovascular and cognitive dysfunction. METHODS: Tg2576 mice and wild-type littermates received intranasal tPA (0.8 mg/kg/day) or vehicle 5 days a week starting at 11 to 12 months of age and were assessed 3 months later. RESULTS: Treatment of Tg2576 mice with tPA restored resting CBF, prevented the attenuation in functional hyperemia, and improved nesting behavior. These effects were associated with reduced cerebral atrophy and cerebral amyloid angiopathy, but not parenchymal amyloid. DISCUSSION: These findings highlight the key role of tPA deficiency in the neurovascular and cognitive dysfunction associated with amyloid pathology, and suggest potential therapeutic strategies involving tPA reconstitution. HIGHLIGHTS: Amyloid beta (Aß) induces neurovascular dysfunction and impairs the increase of cerebral blood flow induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) deficiency contributes to the neurovascular and cognitive dysfunction caused by Aß. In mice with florid amyloid pathology intranasal administration of tPA rescues the neurovascular and cognitive dysfunction and reduces brain atrophy and cerebral amyloid angiopathy. tPA deficiency plays a crucial role in neurovascular and cognitive dysfunction induced by Aß and tPA reconstitution may be of therapeutic value.

Carotid-cavernous fistula: A potential treatable cause of bilateral abducens palsy and conjunctival hyperemia.

OBJECTIVE: Carotid cavernous fistulas (CCFs) represent uncommon and anomalous communications between the carotid artery and the cavernous sinus. MATERIALS AND METHODS: Case report RESULTS: We present the clinical details and successful management of a previously healthy 44-year-old patient who presented with one-month worsening headache, bilateral abducens palsy and conjunctival injection. Imaging modalities including magnetic resonance imaging (MRI) with contrast and digital subtraction angiography (DSA) facilitated the diagnosis of CCF. The patient underwent endovascular coiling of the CCF, leading to neurological recovery and symptom remission. CONCLUSION: This case highlights the importance of promptly CCF diagnosis in patients with multiple cranial nerve palsies and conjunctival hyperemia. Moreover, it emphasizes the efficacy of endovascular coiling in achieving symptom remission.

Optimal Cerebral Perfusion Pressure and Brain Tissue Oxygen in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Targeting a cerebral perfusion pressure optimal for cerebral autoregulation (CPPopt) has been gaining more attention to prevent secondary damage after acute neurological injury. Brain tissue oxygenation (PbtO2) can identify insufficient cerebral blood flow and secondary brain injury. Defining the relationship between CPPopt and PbtO2 after aneurysmal subarachnoid hemorrhage may result in (1) mechanistic insights into whether and how CPPopt-based strategies might be beneficial and (2) establishing support for the use of PbtO2 as an adjunctive monitor for adequate or optimal local perfusion. METHODS: We performed a retrospective analysis of a prospectively collected 2-center dataset of patients with aneurysmal subarachnoid hemorrhage with or without later diagnosis of delayed cerebral ischemia (DCI). CPPopt was calculated as the cerebral perfusion pressure (CPP) value corresponding to the lowest pressure reactivity index (moving correlation coefficient of mean arterial and intracranial pressure). The relationship of (hourly) deltaCPP (CPP-CPPopt) and PbtO2 was investigated using natural spline regression analysis. Data after DCI diagnosis were excluded. Brain tissue hypoxia was defined as PbtO2 <20 mmHg. RESULTS: One hundred thirty-one patients were included with a median of 44.0 (interquartile range, 20.8-78.3) hourly CPPopt/PbtO2 datapoints. The regression plot revealed a nonlinear relationship between PbtO2 and deltaCPP (P<0.001) with PbtO2 decrease with deltaCPP <0 mmHg and stable PbtO2 with deltaCPP ≥0mmHg, although there was substantial individual variation. Brain tissue hypoxia (34.6% of all measurements) was more frequent with deltaCPP <0 mmHg. These dynamics were similar in patients with or without DCI. CONCLUSIONS: We found a nonlinear relationship between PbtO2 and deviation of patients' CPP from CPPopt in aneurysmal subarachnoid hemorrhage patients in the pre-DCI period. CPP values below calculated CPPopt were associated with lower PbtO2. Nevertheless, the nature of PbtO2 measurements is complex, and the variability is high. Combined multimodality monitoring with CPP/CPPopt and PbtO2 should be recommended to redefine individual pressure targets (CPP/CPPopt) and retain the option to detect local perfusion deficits during DCI (PbtO2), which cannot be fulfilled by both measurements interchangeably.

Impaired peripheral microvascular reactivity in patients with nonobstructive coronary artery disease.

OBJECTIVE: This study aimed to determine whether peripheral microvascular reactivity is impaired in patients with nonobstructive coronary artery disease (NOCAD). METHODS: Stable patients presenting with angina were recruited and, based on results from coronary angiography, were categorized into OCAD (coronary stenosis of ≥50%) and NOCAD (stenosis <50%) groups. A control group with no history of angina was also recruited. Forearm skin microvascular reactivity was measured using the laser Doppler blood perfusion monitor and the process of postocclusive skin reactive hyperemia (PORH). RESULTS: Patients were categorized into OCAD (n = 42), NOCAD (n = 40), and control (n = 39) groups. Compared with the control group, the PORH perfusion percent change (PORH% change) was significantly lower in the OCAD and NOCAD groups. No significant differences were noted between the OCAD and NOCAD groups. Additionally, the NOCAD group without any coronary obstruction takes a longer time to reach peak perfusion and had lower PORH% change compared with the nonangina control group. CONCLUSION: Angina patients with NOCAD have microvascular dysfunction as demonstrated by reduced magnitude of reperfusion with an ischemic stimulus. NOCAD patients without coronary obstruction also displayed a slower response to reperfusion.

Muscle Oxygenation and Microvascular Reactivity Across Different Stages of CKD: A Near-Infrared Spectroscopy Study.

RATIONALE & OBJECTIVE: Previous studies in chronic kidney disease (CKD) showed that vascular dysfunction in different circulatory beds progressively deteriorates with worsening CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with different stages of CKD versus controls. STUDY DESIGN: Observational controlled study. SETTING & PARTICIPANTS: 90 participants (18 per CKD stage 2, 3a, 3b, and 4, as well as 18 controls). PREDICTOR: CKD stage. OUTCOME: The primary outcome was muscle oxygenation at rest. Secondary outcomes were muscle oxygenation during occlusion-reperfusion and exercise, and muscle microvascular reactivity (hyperemic response). ANALYTICAL APPROACH: Continuous measurement of muscle oxygenation [tissue saturation index (TSI)] using near-infrared spectroscopy at rest, during occlusion-reperfusion, and during a 3-minute handgrip exercise (at 35% of maximal voluntary contraction). Aortic pulse wave velocity and carotid intima-media thickness were also recorded. RESULTS: Resting muscle oxygenation did not differ across the study groups (controls: 64.3% ± 2.9%; CKD stage 2: 63.8% ± 4.2%; CKD stage 3a: 64.1% ± 4.1%; CKD stage 3b: 62.3% ± 3.3%; CKD stage 4: 62.7% ± 4.3%; P=0.6). During occlusion, no significant differences among groups were detected in the TSI occlusion magnitude and TSI occlusion slope. However, during reperfusion the maximum TSI value was significantly lower in groups of patients with more advanced CKD stages compared with controls, as was the hyperemic response (controls: 11.2%±3.7%; CKD stage 2: 8.3%±4.6%; CKD stage 3: 7.8%±5.5%; CKD stage 3b: 7.3%±4.4%; CKD stage 4: 7.2%±3.3%; P=0.04). During the handgrip exercise, the average decline in TSI was marginally lower in patients with CKD than controls, but no significant differences were detected across CKD stages. LIMITATIONS: Moderate sample size, cross-sectional evaluation. CONCLUSIONS: Although no differences were observed in muscle oxygenation at rest or during occlusion, the microvascular hyperemic response during reperfusion was significantly impaired in CKD and was most prominent in more advanced CKD stages. This impaired ability of microvasculature to respond to stimuli may be a crucial component of the adverse vascular profile of patients with CKD and may contribute to exercise intolerance. PLAIN-LANGUAGE SUMMARY: Previous studies in chronic kidney disease (CKD) have shown that vascular dysfunction in different circulatory beds progressively deteriorates with CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with nondialysis CKD versus controls, as well as across different CKD stages. It showed that the microvascular hyperemic response after an arterial occlusion was significantly impaired in CKD and was worst in patients with more advanced CKD. No significant differences were detected in skeletal muscle oxygenation or muscle oxidative capacity at rest or during the handgrip exercise when comparing patients with CKD with controls or comparing across CKD stages. The impaired ability of microvasculature to respond to stimuli may be a component of the adverse vascular profile of patients with CKD and may contribute to exercise intolerance.

The vascular function effects of adding exenatide or meal insulin to basal insulin therapy in early type 2 diabetes.

OBJECTIVE: Basal insulin glargine has a neutral effect on cardiovascular risk in type 2 diabetes (T2DM). In practice, basal insulin is often paired with a glucagon-like peptide-1 receptor agonist (GLP1-RA) or meal insulin; however, the cardiovascular implications of these combinations have not been fully elucidated. In this context, we sought to evaluate the vascular function effects of adding the GLP1-RA exenatide or meal insulin lispro to basal glargine therapy in early T2DM. METHODS: In this 20-week trial, adults with T2DM of < 7-years duration were randomized to 8-weeks treatment with (i) insulin glargine (Glar), (ii) glargine + thrice-daily lispro (Glar/Lispro), or (iii) glargine + twice-daily exenatide (Glar/Exenatide), followed by 12-weeks washout. At baseline, 8-weeks, and washout, fasting endothelial function was assessed with reactive hyperemia index (RHI) measurement by peripheral arterial tonometry. RESULTS: At baseline, there were no differences in blood pressure (BP), heart rate (HR) or RHI between participants randomized to Glar (n = 24), Glar/Lispro (n = 24), and Glar/Exenatide (n = 25). At 8-weeks, Glar/Exenatide decreased systolic BP (mean - 8.1 mmHg [95%CI - 13.9 to - 2.4], p = 0.008) and diastolic BP (mean - 5.1 mmHg [- 9.0 to - 1.3], p = 0.012) compared to baseline, with no significant changes in HR or RHI. Notably, baseline-adjusted RHI (mean ± SE) did not differ between the groups at 8-weeks (Glar 2.07 ± 0.10; Glar/Lispro 2.00 ± 0.10; Glar/Exenatide 1.81 ± 0.10; p = 0.19), nor did baseline-adjusted BP or HR. There were no differences between the groups in baseline-adjusted RHI, BP or HR after 12-weeks washout. CONCLUSION: Adding either exenatide or lispro to basal insulin therapy does not appear to affect fasting endothelial function in early T2DM. TRIAL REGISTRATION: ClinicalTrials.Gov NCT02194595.

Alcohol consumption and microvascular dysfunction: a J-shaped association: The Maastricht Study.

BACKGROUND: Microvascular dysfunction (MVD) is an important contributor to major clinical disease such as stroke, dementia, depression, retinopathy, and chronic kidney disease. Alcohol consumption may be a determinant of MVD. OBJECTIVE: Main objectives were (1) to study whether alcohol consumption was associated with MVD as assessed in the brain, retina, skin, kidney and in the blood; and (2) to investigate whether associations differed by history of cardiovascular disease or sex. DESIGN: We used cross-sectional data from The Maastricht Study (N = 3,120 participants, 50.9% men, mean age 60 years, and 27.5% with type 2 diabetes [the latter oversampled by design]). We used regression analyses to study the association between total alcohol (per unit and in the categories, i.e. none, light, moderate, high) and MVD, where all measures of MVD were combined into a total MVD composite score (expressed in SD). We adjusted all associations for potential confounders; and tested for interaction by sex, and history of cardiovascular disease. Additionally we tested for interaction with glucose metabolism status. RESULTS: The association between total alcohol consumption and MVD was non-linear, i.e. J-shaped. Moderate versus light total alcohol consumption was significantly associated with less MVD, after full adjustment (beta [95% confidence interval], -0.10 [-0.19; -0.01]). The shape of the curve differed with sex (Pinteraction = 0.03), history of cardiovascular disease (Pinteraction < 0.001), and glucose metabolism status (Pinteraction = 0.02). CONCLUSIONS: The present cross-sectional, population-based study found evidence that alcohol consumption may have an effect on MVD. Hence, although increasing alcohol consumption cannot be recommended as a policy, this study suggests that prevention of MVD may be possible through dietary interventions.

Reactive hyperemia half-time response is associated with skeletal muscle oxygen saturation changes during cycling exercise.

We investigated the relationship between muscle microvascular responses during reactive hyperemia as assessed using near-infrared spectroscopy (NIRS) with changes in skeletal muscle oxygen saturation during exercise. Thirty young untrained adults (M/W: 20/10; 23 ± 5 years) completed a maximal cycling exercise test to determine exercise intensities performed on a subsequent visit separated by seven days. At the second visit, post-occlusive reactive hyperemia was measured as changes in NIRS-derived tissue saturation index (TSI) at the left vastus lateralis muscle. Variables of interest included desaturation magnitude, resaturation rate, resaturation half-time, and hyperemic area under the curve. Afterwards, two 4-minute bouts of moderate intensity cycling followed by one bout of severe intensity cycling to fatigue took place while TSI was measured at the vastus lateralis muscle. TSI was averaged across the last 60-s of each moderate intensity bout then averaged together for analysis, and at 60-s into severe exercise. The change in TSI (∆TSI) during exercise is expressed relative to a 20 W cycling baseline. On average, the ΔTSI was -3.4 ± 2.4 % and -7.2 ± 2.8 % during moderate and severe intensity cycling, respectively. Resaturation half-time was correlated with the ΔTSI during moderate (r = -0.42, P = 0.01) and severe (r = -0.53, P = 0.002) intensity exercise. No other reactive hyperemia variable was found to correlate with ΔTSI. These results indicate that resaturation half-time during reactive hyperemia represents a resting muscle microvascular measure that associates with the degree of skeletal muscle desaturation during exercise in young adults.

Association Between Endothelial Dysfunction and Left Ventricular Diastolic Stiffness　- Subanalysis of the Flow-Mediated Dilation Japan (FMD-J) Study.

BACKGROUND: Endothelial dysfunction and increased left ventricular (LV) stiffness are associated with the incidence of heart failure with preserved ejection fraction (HFpEF). This study evaluated the association between endothelial dysfunction and LV diastolic stiffness.Methods and Results: Endothelial dysfunction evaluated by flow-medicated vasodilation (FMD) and the reactive hyperemia index (RHI), which reflects endothelial dysfunction in the microvasculature, was measured in 112 subjects with hypertension in the Flow-Mediated Dilation Japan (FMD-J) study. Using transthoracic echocardiography, LV diastolic stiffness was evaluated by measuring diastolic wall strain (DWS) in the LV posterior wall. In this cross-sectional study, associations among FMD, RHI, and DWS were investigated using multiple regression analyses. The mean (±SD) age of the subjects 65±9 years, and 63% were men. DWS was significantly associated with RHI, but not FMD, on multivariate linear regression analysis (ß=0.39; P<0.0001). This association was preserved in subjects without LV hypertrophy (ß=0.46; P<0.0001). A DWS ≤median, suggesting increased LV diastolic stiffness, was significantly associated with RHI on multivariate logistic regression analysis (odds ratio 20.58; 95% confidence interval 4.83-87.63; P<0.0001). The receiver operating characteristic curve presented a cut-off value of 2.21 for RHI, with a sensitivity of 77% and a specificity of 71%, for DWS ≤median. CONCLUSIONS: RHI, rather than FMD, was associated with DWS. Endothelial dysfunction in the microvasculature may be associated with increased LV diastolic stiffness.

Arterial occlusion duration affects the cuff-induced hyperemic response in skeletal muscle BOLD perfusion imaging as shown in young healthy subjects.

OBJECTIVE: Dynamic BOLD MRI with cuff compression, inducing ischemia and post-occlusive hyperemia in skeletal muscle, has been pointed out as a potential diagnostic tool to assess peripheral limb perfusion. The objective was to explore the robustness of this technique and its sensitivity to the occlusion duration. MATERIALS AND METHODS: BOLD images were acquired at 3 T in 14 healthy volunteers. [Formula: see text]-imaging with 5- and 1.5-min occlusions were acquired and several semi-quantitative BOLD parameters were derived from ROI-based [Formula: see text]-time curves. Differences in parameters from the two different occlusion durations were evaluated in the gastrocnemius and soleus muscles using non-parametrical tests. Intra- and inter-scan repeatability were evaluated with coefficient of variation. RESULTS: Longer occlusion duration resulted in an increased hyperemic signal effect yielding significantly different values (p < 0.05) in gastrocnemius for all parameters describing the hyperemic response, and in soleus for two of these parameters. Specifically, 5-min occlusion yielded steeper hyperemic upslope in gastrocnemius (41.0%; p < 0.05) and soleus (59.7%; p = 0.03), shorter time to half peak in gastrocnemius (46.9%; p = 0.00008) and soleus (33.5%; p = 0.0003), and shorter time to peak in gastrocnemius (13.5%; p = 0.02). Coefficients of variation were lower than percentage differences that were found significant. DISCUSSION: Findings show that the occlusion duration indeed influences the hyperemic response and thus should play a part in future methodological developments.

Increased soluble endoglin levels in newly-diagnosed type 2 diabetic patients are associated with endothelial dysfunction.

Endothelial dysfunction (ED) contributes to the pathologic process underlying macrovascular complications, a common complication of type 2 diabetes mellitus (T2DM). Soluble endoglin (sEng) shed from the extracellular domain of the entire endoglin molecule blocks endothelial protection mediated by transforming growth factor-beta 1 (TGF-ß1). The reactive hyperemia index (RHI), which is determined by reactive hyperemia peripheral arterial tonometry (RH-PAT), is a new index with which to evaluate ED. This study determined the changes in serum sEng levels in newly-diagnosed (untreated) T2DM patients and the correlation with the RHI. The T2DM group included 34 newly-diagnosed T2DM patients, while the control group included 53 healthy adults. The clinical data from the two groups were evaluated retrospectively. The intima-media thickness (IMT) of the common carotid artery (CCA) and the ankle-brachial index (ABI) of both legs were used to assess structural vascular changes. The serum sEng level was determined using an ELISA kit. Endothelial function was assessed using RH-PAT and the RHI was computed. The serum sEng level in the T2DM group was significantly greater than the control group, although the RHI was significantly lower in the T2DM group (p < 0.05). The serum sEng level was negatively correlated with the RHI in T2DM patents (r = 0.354, p = 0.041). The serum sEng level, CCA-IMT, and ABI were not significantly correlated with T2DM (p > 0.05). In summary, among newly-diagnosed T2DM patients, the serum sEng levels were inversely correlated with the RHI, and an elevated sEng level may be associated with ED.

Spectral analysis of laser speckle contrast imaging and infrared thermography to assess skin microvascular reactive hyperemia.

BACKGROUND: Post-occlusive reactive hyperemia (PORH) test with signal spectral analysis coupled provides potential indicators for the assessment of microvascular functions. OBJECTIVE: The objective of this study is to investigate the variations of skin blood flow and temperature spectra in the PORH test. Furthermore, to quantify the oscillation amplitude response to occlusion within different frequency ranges. MATERIALS AND METHODS: Ten healthy volunteers participated in the PORH test and their hand skin temperature and blood flow images were captured by infrared thermography (IRT) and laser speckle contrast imaging (LSCI) system, respectively. Extracted signals from selected areas were then transformed into the time-frequency space by continuous wavelet transform for cross-correlation analysis and oscillation amplitude response comparisons. RESULTS: The LSCI and IRT signals extracted from fingertips showed stronger hyperemia response and larger oscillation amplitude compared with other areas, and their spectral cross-correlations decreased with frequency. According to statistical analysis, their oscillation amplitudes in the PORH stage were obviously larger than the baseline stage within endothelial, neurogenic, and myogenic frequency ranges (p < 0.05), and their quantitative indicators of oscillation amplitude response had high linear correlations within endothelial and neurogenic frequency ranges. CONCLUSION: Comparisons of IRT and LSCI techniques in recording the reaction to the PORH test were made in both temporal and spectral domains. The larger oscillation amplitudes suggested enhanced endothelial, neurogenic, and myogenic activities in the PORH test. We hope this study is also significant for investigations of response to the PORH test by other non-invasive techniques.