Hypertension Likely Drives Arteriolar Wall Thickening in Preclinical Diabetic Retinopathy While Diabetes Drives Wall Thickness in Clinical Retinopathy.

Purpose: Both hypertension and diabetes are known to increase the wall-to-lumen ratio (WLR) of retinal arterioles, but the differential effects are unknown. Here, we study the timing and relative impact of hypertension versus diabetes on the WLR in diabetic retinopathy (DR) to address this unresolved question. Methods: This prospective cross-sectional study compared the retinal arteriolar WLR in 17 healthy eyes, 15 with diabetes but no apparent DR (DM no DR), and 8 with diabetic macular edema (DME) and either nonproliferative or proliferative DR. We imaged each arteriole using adaptive optics scanning laser ophthalmoscopy and measured the WLR using ImageJ. Multiple linear regression (MLR) was performed to estimate the effects of hypertension, diabetes, and age on the WLR. Results: Both subjects with DM no DR and subjects with DME had significantly higher WLR than healthy subjects (0.36 ± 0.08 and 0.42 ± 0.08 vs. 0.29 ± 0.07, 1-way ANOVA P = 0.0009). MLR in healthy subjects and subjects with DM no DR showed hypertension had the strongest effect (regression coefficient = 0.08, P = 0.009), whereas age and diabetes were not significantly correlated with WLR. MLR in all three groups together (healthy, DM no DR, and DME) showed diabetes had the strongest effect (regression coefficient = 0.05, P = 0.02), whereas age and hypertension were not significantly correlated with WLR. Conclusions: Hypertension may be an early driver of retinal arteriolar wall thickening in preclinical DR, independent of age or diabetes, whereas changes specific to DR may drive wall thickening in DME and later DR stages. Translational Relevance: We offer a framework for understanding the relative contributions of hypertension and diabetes on the vascular wall, and emphasize the importance of hypertension control early in diabetes even before DR onset.

Prognostic significance of the wall to lumen ratio of retinal arterioles evaluated by adaptive optics.

OBJECTIVE: Microvascular structural alterations may be considered an important form of hypertension-mediated organ damage. An increased media-to-lumen ratio of subcutaneous small arteries evaluated with locally invasive techniques (micromyography) predicts the development of cardiovascular (CV) events. However, it is not known whether retinal arteriole structural alterations evaluated with a noninvasive approach (Adaptive Optics) may have a prognostic significance. DESIGN AND METHODS: Two-hundred and thirty-seven subjects (mean age 58.7 ± 16.1 years, age range 13-89 years; 116 males) were included in the study: 65 normotensive subjects (27.4 %) and 172 patients with essential hypertension or primary aldosteronism (72.6 %). All subjects underwent a non-invasive evaluation of retinal arteriolar wall-to-lumen ratio (WLR) by Adaptive Optics. Subjects were re-evaluated after an average follow-up time of 4.55 years in order to assess the occurrence of clinical events (non CV and/or CV death or events). RESULTS: Fifty-four events occurred in the study population:26 were cardio-cerebrovascular events (ischemic or hemorragic stroke, atrial fibrillation, heart failure, coronary artery disease, peripheral artery disease, cardiac valvular disease) while the remaining were deaths for any cause, or neoplastic diseases. Subjects with events were older and had a WLR of retinal arterioles significantly greater than those without events. The event-free survival was significantly worse in those with a baseline WLR above the median value of the population (0.28) according to Kaplan-Mayer survival curves and multivariate analysis (Cox's proportional hazard model). The evidence was confirmed after restricting the analysis to CV events. CONCLUSIONS: Structural alterations of retinal arterioles evaluated by Adaptive Optics may predict total and CV events.

Retinal Arteriolar Occlusions and Exudative Retinal Detachments in Malignant Hypertension: More Than Meets the Eye.

BACKGROUND: Malignant hypertension is macrovascular and microvascular endothelial injury responsible for multiple organ damage. Considering the anatomical and functional homologies between the posterior pole of the eye and the kidney, ophthalmological explorations may inform clinicians on the mechanisms underpinning concurrent kidney injury in this condition. More specifically, we investigated whether the wall-to-lumen ratio (WLR) of retinal arterioles measured by adaptive optics ophthalmoscopy could be correlated to WLR of kidney arterioles as determined by pathology. We sought to estimate the incidence of retinal arteriole occlusion a supposedly uncommon complication of malignant hypertension. METHODS: All patients hospitalized in our renal Intensive Care Unit for malignant hypertension between 2016 and 2019 were referred to ophthalmological examinations. RESULTS: Twenty-seven patients were included. Median retinal WLR was 0.39 [0.31-0.47] and was correlated with initial systolic (r = 0.56, P = 0.003) and mean blood pressure (r = 0.46, P = 0.02) upon admission. The retinal WLR was not correlated to renal pathological findings, as assessed by juxtaglomerular WLR (r = 0.38, P = 0.2), ratio of glomerulosclerosis (r = -0.39, P = 0.2), or tubulointerstitial fibrosis (r = -0.45, P = 0.08). Retinal WLR was not associated with neurological or cardiovascular end-organ damage. Branch retinal artery occlusion was detected in 18.5% of patients and exudative retinal detachment (ERD) in 29.6% of patients, without any significant correlation with canonical signs of retinal hypertension including optic disc swelling. CONCLUSIONS: In the setting of malignant hypertension, we failed to demonstrate a significant relationship between WLR and other meaningful end-organ injuries. However, branch retinal artery occlusion and ERD may have been hitherto underestimated.

The capability of detecting small vessels beyond the conventional MRI sensitivity using iron-based contrast agent enhanced susceptibility weighted imaging.

Imaging brain microvasculature is important in cerebrovascular diseases. However, there is still a lack of non-invasive, non-radiation, and whole-body imaging techniques to investigate them. The aim of this study is to develop an ultra-small superparamagnetic iron oxide (USPIO) enhanced susceptibility weighted imaging (SWI) method for imaging micro-vasculature in both animal (~10 µm in rat) and human brain. We hypothesized that the USPIO-SWI technique could improve the detection sensitivity of the diameter of small subpixel vessels 10-fold compared with conventional MRI methods. Computer simulations were first performed with a double-cylinder digital model to investigate the theoretical basis for this hypothesis. The theoretical results were verified using in vitro phantom studies and in vivo rat MRI studies (n = 6) with corresponding ex vivo histological examinations. Additionally, in vivo human studies (n = 3) were carried out to demonstrate the translational power of the USPIO-SWI method. By directly comparing the small vessel diameters of an in vivo rat using USPIO-SWI with the small vessel diameters of the corresponding histological slide using laser scanning confocal microscopy, 13.3-fold and 19.9-fold increases in SWI apparent diameter were obtained with 5.6 mg Fe/kg and 16.8 mg Fe/kg ferumoxytol, respectively. The USPIO-SWI method exhibited its excellent ability to detect small vessels down to about 10 µm diameter in rat brain. The in vivo human study unveiled hidden arterioles and venules and demonstrated its potential in clinical practice. Theoretical modeling simulations and in vitro phantom studies also confirmed a more than 10-fold increase in the USPIO-SWI apparent diameter compared with the actual small vessel diameter size. It is feasible to use SWI blooming effects induced by USPIO to detect small vessels (down to 10 µm in diameter for rat brain), well beyond the spatial resolution limit of conventional MRI methods. The USPIO-SWI method demonstrates higher potential in cerebrovascular disease investigations.

IN VIVO OBSERVATION OF RETINAL VASCULAR DEPOSITS USING ADAPTIVE OPTICS IMAGING IN FABRY DISEASE.

PURPOSE: To report a novel finding in patients with Fabry disease, that is, the observation by adaptive optics ophthalmoscopy of intracellular lipidic deposits in retinal vessels. METHODS: Observational two-center case series. Eighteen patients with genetically proven Fabry disease underwent flood-illumination adaptive optics ophthalmoscopy imaging (rtx1; Imagine Eyes, Orsay, France) of retinal vessels. RESULTS: Fourteen patients (78% of all patients; 7 of the 10 women and 7 of the 8 men) showed paravascular punctuate or linear opacities in both eyes. In the least-affected patients, these were seen only in the wall of precapillary arterioles as discrete spots of 5 µm to 10 µm large, whereas in those more severely affected, capillaries and first-order vessels were also involved with diffuse opacification of the wall. These deposits sometime showed a striated pattern, suggesting colocalization with vascular smooth muscle cells. CONCLUSION: Adaptive optics ophthalmoscopy of retinal vessels may be of interest for patients with Fabry disease, providing noninvasive, gradable evaluation of microvascular involvement.

Visualising peripheral arterioles and venules through high-resolution and large-area photoacoustic imaging.

Photoacoustic (PA) imaging (PAI) has been shown to be a promising tool for non-invasive blood vessel imaging. A PAI system comprising a hemispherical detector array (HDA) has been reported previously as a method providing high morphological reproducibility. However, further improvements in diagnostic capability will require improving the image quality of PAI and fusing functional and morphological imaging. Our newly developed PAI system prototype not only enhances the PA image resolution but also acquires ultrasonic (US) B-mode images at continuous positions in the same coordinate axes. In addition, the pulse-to-pulse alternating laser irradiation shortens the measurement time difference between two wavelengths. We scanned extremities and breasts in an imaging region 140 mm in diameter and obtained 3D-PA images of fine blood vessels, including arterioles and venules. We could estimate whether a vessel was an artery or a vein by using the S-factor obtained from the PA images at two wavelengths, which corresponds approximately to the haemoglobin oxygen saturation. Furthermore, we observed tumour-related blood vessels around breast tumours with unprecedented resolution. In the future, clinical studies with our new PAI system will help to elucidate various mechanisms of vascular-associated diseases and events.

Pseudoaneurysm associated with arteriovenous fistula involving a superficial breast arteriole after vacuum-assisted removal of a benign mass: A case report.

RATIONALE: Pseudoaneurysm (PA) with associated arteriovenous fistula (AVF) is most often secondary to vascular catheterization, percutaneous biopsy, surgery, or trauma. PA-AVF occurs mainly in large or median arterial territories but rarely in the superficial arterioles of the breast. PATIENT CONCERNS: A 30-year-old woman underwent vacuum-assisted removal of breast fibroadenomas under ultrasonic guidance. On the follow-up visit, the patient complained of a painful enlarging lump in her left breast. DIAGNOSES: An iatrogenic breast PA-AVF was diagnosed. INTERVENTIONS: The patient was treated with surgical excision and ligation under local anesthesia. OUTCOMES: At the 1-month follow-up, the wound was found to have healed well, and breast PA-AVF was eradicated. LESSONS: Vacuum-assisted removal has been the first-line intervention for benign mass resection because of minimal invasion, but the risk of serious vascular complications remains. Careful duplex ultrasound examination prior to the procedure is highly recommended.

Optical Coherence Tomography Angiography of Familial Retinal Arteriolar Tortuosity.

BACKGROUND AND OBJECTIVE: To analyze the location of familial retinal arterial tortuosity (fRAT) in the three-dimensional structure of retinal capillaries. PATIENTS AND METHODS: Retrospective observational study. Twelve eyes of six patients (two of whom were brothers) were imaged by optical coherence tomography angiography (OCTA). The data from their ocular and systemic examinations were recorded. RESULTS: OCTA imaging clearly showed increased tortuosity of second- and third-order retinal arteries in all cases, visible in the superficial vascular plexus (SVP) up to the arteriole termination in the capillaries. No change was visible in the deep capillary plexus (DCP). CONCLUSIONS: OCTA shows that fRAT affects all the course of the arterioles up to the capillaries in the SVP. The DCP does not show arteriolar tortuosity because it does not contain arterioles. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:397-401.].

Comparison between invasive and noninvasive techniques of evaluation of microvascular structural alterations.

BACKGROUND: The evaluation of the morphological characteristics of small resistance arteries in humans is challenging. The gold standard method is generally considered to be the measurement by wire or pressure micromyography of the media-to-lumen ratio of subcutaneous small vessels obtained by local biopsies. However, noninvasive techniques for the evaluation of retinal arterioles were recently proposed; in particular, two approaches, scanning laser Doppler flowmetry (SLDF) and adaptive optics, seem to provide useful information; both of them provide an estimation of the wall-to-lumen ratio (WLR) of retinal arterioles. Moreover, a noninvasive measurement of basal and total capillary density may be obtained by videomicroscopy/capillaroscopy. No direct comparison of these three noninvasive techniques in the same population was previously performed; in particular, adaptive optics was never validated against micromyography. METHODS: In the current study, we enrolled 41 controls and patients: 12 normotensive lean controls, 12 essential hypertensive lean patients, nine normotensive obese patients and eight hypertensive obese patients undergoing elective surgery. All patients underwent a biopsy of subcutaneous fat during surgery. Subcutaneous small resistance artery structure was assessed by wire micromyography and the media-to-lumen ratio was calculated. WLR of retinal arterioles was obtained by SLDF and adaptive optics. Functional (basal) and structural (total) microvascular density was evaluated by capillaroscopy before and after venous congestion. RESULTS AND CONCLUSION: Our data suggest that adaptive optics has a substantial advantage over SLDF in terms of evaluation of microvascular morphology, as WLR measured with adaptive optics is more closely correlated with the M/L of subcutaneous small arteries (r = 0.84, P < 0.001 vs. r = 0.52, P < 0.05, slopes of the relations: P < 0.01 adaptive optics vs. SLDF). In addition, the reproducibility of the evaluation of the WLR with adaptive optics is far better, as compared with SLDF, as intraobserver and interobserver variation coefficients are clearly smaller. This may be important in terms of clinical evaluation of microvascular morphology in a clinical setting, as micromyography has substantial limitations in its clinical application due to the local invasiveness of the procedure.

Microcirculatory Bed, Microcirculation, and Smoking-Associated Endothelial Dysfunction in Young Adults.

Computer-assisted video biomicroscopy of bulbar conjunctiva was employed to examine the sequelae of endothelial dysfunction manifested by microcirculatory bed abnormalities and microcirculation disturbances. The signs of endothelial dysfunction provoked by tobacco smoking in young adults disappeared after cessation of smoking, which resulted in pronounced widening of arterioles and capillaries as well as moderation of intravascular erythrocyte aggregation.

Calciphylaxis: Comparison of radiologic imaging and histopathology.

BACKGROUND: The current gold standard for diagnosis of calciphylaxis is a skin biopsy specimen demonstrating calcification of small-caliber arteries or arterioles. OBJECTIVE: The aim of this study is to compare diameters of calcified vessels seen in skin biopsy specimens and radiology images of patients with calciphylaxis. METHODS: We conducted a retrospective study of patients with known calciphylaxis from 2009 to 2016 at a community hospital who had both skin biopsy specimens and radiology images taken as part of their routine care. Vascular calcification was compared in skin biopsy specimens and radiology images. RESULTS: Seven patients were identified. Small-vessel calcification as fine as 0.1 to 0.3 mm was identified on plain films in 3 patients; 0.1 to 0.2 mm by mammography in 3 patients, and 0.1 to 0.2 mm by computed tomography imaging in 1 patient, nearly as fine a resolution as on histopathology. LIMITATIONS: This was a single-center study with limited sample size. CONCLUSION: Radiologic imaging might enable more rapid diagnosis of calciphylaxis when skin biopsy specimen is pending or not available.

Renal contrast microangiography with synchrotron radiation: a novel method for visualizing structures within nephrons in vivo.

Background No non-invasive method of observing renal microcirculation in vivo has been established as yet. Although angiography is considered to be ideally suited for the purpose, conventional X-rays cannot be used to image structures smaller than 100 µm. Purpose To develop a method for visualizing the renal arterioles, glomeruli, and proximal tubules of rats in vivo making use of synchrotron radiation. Material and Methods Male Wistar rats were anesthetized, and a catheter was inserted via laparotomy into the abdominal aorta with its tip placed above the renal arteries. The rats were paralyzed with a neuromuscular blocking agent and mechanically ventilated. An inorganic iodine contrast medium was injected via the catheter. The SR derived X-rays transmitted through the subjects were recorded with a CCD camera. Two-dimensional images with a pixel size of 9 µm were obtained. The exposure time was fixed at 50 ms, with a maximum acquisition rate of three images/s. Results Renal arterioles as small as 18 µm in diameter, glomeruli with an average diameter of 173 ± 21 µm, as well as proximal tubules, were clearly visualized. In addition, glomerular density at the peripheral renal cortex was measurable. Conclusion Rat renal microcirculation could be successfully observed in real-time, without exteriorization of the kidney in this study.

The Systemic Blood Pressure and Oxygen Saturation in Retinal Arterioles Predict the Effect of Intravitreal Anti-VEGF Treatment on Diabetic Maculopathy.

PURPOSE: The advent of vascular endothelial VEGF antagonists has increased the therapeutic options for diabetic maculopathy considerably. However, there is a need to identify patients who respond favorably to the treatment from those in whom the treatment is less effective. The purpose of the present study was to test the hypothesis that the oxygen saturation in retinal vessels together with other risk factors can predict the effect of anti-VEGF treatment on diabetic maculopathy. METHODS: In 73 eyes from 53 patients with center-involving diabetic macular edema, multiple linear regression was used to evaluate the predictive value of oxygen saturation in larger retinal vessels together with age, diabetes duration, diabetes type, hemoglobin A1c (HbA1c), mean arterial blood pressure (MAP), body mass index (BMI), previous retinal photocoagulation, visual acuity (VA), and central retinal thickness (CRT) before treatment as explanatory variables for VA and CRT after three monthly injections of anti-VEGF medication. RESULTS: Anti-VEGF treatment induced a significant increase in VA and a significant decrease in CRT, but no significant changes in the overall oxygen saturation of larger retinal vessels. Visual acuity and CRT before treatment contributed significantly to predicting the same variable after treatment. Additionally, MAP and the oxygen saturation in retinal arterioles before treatment contributed significantly to predicting VA and CRT after treatment. CONCLUSIONS: The MAP and oxygen saturation in retinal arterioles might potentially be included as parameters in risk models predicting the effect of anti-VEGF treatment in patients with diabetic maculopathy.

Association between endothelial function and micro-vascular remodeling measured by synchrotron radiation pulmonary micro-angiography in pulmonary arterial hypertension.

OBJECTIVES: Pulmonary arterial hypertension (PAH) is a progressive disease which causes increased vascular resistance. In this study, our purpose was to quantify the micro-vascular remodeling in monocrotaline-induced PAH rats using synchrotron radiation pulmonary micro-angiography (SRPA), a method we have previously established in an in vivo rat model. To determine the relationship between endothelial function and vascular remodeling, the local expression of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) was evaluated using immunohistochemical staining. METHODS: Monocrotaline-induced PAH rats were created by subcutaneous injection of monocrotaline. After 2 weeks, SRPA was performed at the Photon Factory of the High Energy Accelerator Research Organization. The internal diameters of pulmonary arterioles were measured using SRPA images. Semi-quantified analyses of ET-1, eNOS and VEGF expression in pulmonary arterioles were performed by immunohistochemical staining. RESULTS: Micro-vascular density and the internal diameters of pulmonary arterioles were significantly decreased in PAH. ET-1 expression was significantly increased in PAH compared with the control (1.53 ± 0.45 vs. 0.80 ± 0.14) and eNOS expression was significantly decreased in PAH compared with the control (1.12 ± 0.59 vs. 1.91 ± 0.66), although VEGF expression did not differ between the groups. CONCLUSIONS: SRPA can be effectively used for visualizing the decreased pulmonary micro-vasculature associated with PAH. Increased ET-1 expression and decreased eNOS expression may contribute to the proliferation and vasospasm of pulmonary arterioles induced by endothelial dysfunction due to PAH. This SRPA technology may help to identify a correlation between endothelial function and micro-vasculature remodeling in PAH.

Measurement of arteriolar blood volume in brain tumors using MRI without exogenous contrast agent administration at 7T.

PURPOSE: Arteriolar cerebral-blood-volume (CBVa) is an important perfusion parameter that can be measured using inflow-based vascular-space-occupancy (iVASO) MRI without exogenous contrast agent administration. The purpose of this study is to assess the potential diagnostic value of CBVa in brain tumor patients by comparing it with total-CBV (including arterial, capillary and venous vessels) measured by dynamic-susceptibility-contrast (DSC) MRI. MATERIALS AND METHODS: Twelve brain tumor patients were scanned using iVASO (on 7T as part of a research project) and DSC (on 3T as part of routine clinical protocols) MRI. Region-of-interest analysis was performed to compare the resulting perfusion measures between tumoral and contralateral regions, and to evaluate their associations with tumor grades. RESULTS: CBVa measured by iVASO MRI significantly correlated with WHO grade (ρ = 0.37, P = 0.04). Total-CBV measured by DSC MRI showed a trend of correlation with WHO grade (ρ = 0.28, P = 0.5). The signal-to-noise ratio was comparable (P > 0.1) between the two methods, while the contrast-to-noise ratio between tumoral and contralateral regions was higher in iVASO-CBVa than DSC-CBV in WHO II/III patients (P < 0.05) but comparable in WHO IV patients (P > 0.1). A trend of positive correlation between DSC-CBV and iVASO-CBVa was observed (R2 = 0.28, P = 0.07). CONCLUSION: In this initial patient study, CBVa demonstrated a stronger correlation with WHO grade than total-CBV. Further investigation with a larger cohort is warranted to validate whether CBVa can be a better classifier than total-CBV for the stratification of brain tumors, and whether iVASO MRI can be a useful alternative method for the assessment of tumor perfusion, especially when exogenous contrast agent administration is difficult in certain patient populations. J. Magn. Reson. Imaging 2016;44:1244-1255.

Meaningful correlation between asymptomatic retinal arteriole emboli and calcified carotid plaque found on panoramic dental imaging of males with diabetes.

OBJECTIVE: There is ongoing controversy with regard to the stability of calcified carotid artery plaques (CCAPs) seen in the bifurcation area on panoramic images (PIs). Therefore, we sought to evaluate the possibility of these plaques shedding emboli by observing their relationship with ipsilateral retinal emboli. STUDY DESIGN: The study group included 50 neurologically and visually asymptomatic males with diabetes, with PIs that incidentally demonstrated CCAPs (CCAP+) and contemporaneous digital retinal images that had been obtained for evaluation of diabetic retinopathy. The control group consisted of 50 males with diabetes who were matched for age and body mass index and had undergone both imaging studies and whose PIs were devoid of carotid plaques (CCAP-). The presence of retinal emboli was determined by two ophthalmologists blinded to the patients' medical histories, and the prevalence rates for the two groups were calculated. RESULTS: The presence of asymptomatic retinal arteriolar emboli was found in the eye ipsilateral to the radiographically observed carotid atheroma in 10 of 50 (20%) of the patients in the CCAP+ group, compared with 2 of 50 (4%) in the CCAP- group, and this difference was statistically significant (Fisher's exact P < .03). CONCLUSIONS: Some male patients with diabetes mellitus type II having calcified carotid artery atheromas in the bifurcation area, as visualized on PIs, may have significant sequelae as evidenced by retinal artery emboli.

Development of Fingertip Synchrotron Radiation Microangiography toward Clinical Prediction of Diabetic Microangiopathy.

OBJECTIVES: The spatial resolution of conventional angiographic systems is not enough to predict diabetic microangiopathy in arterioles (20-200 µm). METHODS: To determine whether fingertip synchrotron (SR) radiation microangiography has enough spatial resolution to quantitate arteriolar diameter changes, and whether an arteriolar paradoxical vasoconstriction is a characteristic observation for diabetic microangiopathy, diameter reduction as arteriolar branching and difference of the diameter changes induced by acetylcholine between control (n = 5) and diabetic rats (n = 5) were analyzed. RESULTS: Fingertip SR microangiography visualized the arterioles with a diameter range of 30-300 µm and demonstrated vascular diameter reduction as branching with a fixed ratio (r = 0.93, P < 0.004 and r = 0.73, P < 0.001). A vasodilatory reaction was induced by acetylcholine in the control (142.4 ± 61.9 to 190.9 ± 73.5, P < 0.05, n = 25), in contrast, paradoxical vasoconstriction in diabetic rats (201.6 ± 83.0 to 16 0.4 ± 67.9, P < 0.05, n = 37). Histological angiopathy was noted only in the diabetic rats. CONCLUSION: In conclusion, the fingertip SR microangiography is useful to predict diabetic micrangiopahty.

Correlation of carotid artery disease severity and vasomotor response of cerebral blood vessels.

We assessed reactivity of cerebral vessels on hypercapnia in patients with carotid occlusive disease. The effects of vascular risk factors on carotid atherosclerosis and vasomotor reactivity (VMR) of cerebral arterioles were also examined. Patients (n = 50) with carotid stenosis (≥30% in 1 or both sides) were included; 30 patients acted as controls. Hypertension, hyperlipidemia, diabetes, cardiac diseases, inflammation, and smoking were recorded. Vasomotor reactivity was assessed with the apnea test by transcranial Doppler ultrasonography and estimated by flow velocity changes in the middle cerebral artery before and after hypercapnia induction. Vasomotor reactivity was defined by the breath holding index, and values under 0.69 were considered critical for VMR impairment. Vasomotor reactivity reduction was significant (P = .004) in patients with severe carotid stenosis (>70%) and with symptomatic carotid disease (P < .05). The risk factors did not significantly influence VMR reduction. Severe carotid stenosis impairs VMR and may increase the risk of stroke, especially in symptomatic patients.