Georges Leftheriotis

Effect of acute sleep deprivation on vascular function in healthy subjects

Sleep disorders are associated with inflammation and sympathetic activation, which are suspected to induce endothelial dysfunction, a key factor in the increased risk of cardiovascular disease. Less is known about the early effects of acute sleep deprivation on vascular function. We evaluated microvascular reactivity and biological markers of endothelial activation during continuous 40 h of total sleep deprivation (TSD) in 12 healthy men (29 +/- 3 yr). The days before [day 1 (D1)] and during TSD (D3), at 1200 and 1800, endothelium-dependent and -independent cutaneous vascular conductance was assessed by iontophoresis of acetylcholine and sodium nitroprusside, respectively, coupled to laser-Doppler flowmetry. At 0900, 1200, 1500, and 1800, heart rate (HR) and instantaneous blood pressure (BP) were recorded in the supine position. At D1, D3, and the day after one night of sleep recovery (D4), markers of vascular endothelial cell activation, including soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and interleukin-6 were measured from blood samples at 0800. Compared with D1, plasma levels of E-selectin were raised at D3, whereas intercellular adhesion molecule-1 and interleukin-6 were raised at D4 (P < 0.05). The endothelium-dependent and -independent CVC were significantly decreased after 29 h of TSD (P < 0.05). By contrast, HR, systolic BP, and the normalized low-frequency component of HR variability (0.04-0.15 Hz), a marker of the sympathetic activity, increased significantly within 32 h of TSD (P < 0.05). In conclusion, acute exposure to 40 h of TSD appears to cause vascular dysfunction before the increase in sympathetic activity and systolic BP.

Assessment of skin microvascular function and dysfunction with laser speckle contrast imaging.

In recent years, skin microcirculation has been considered an easily accessible and potentially representative vascular bed to evaluate and understand the mechanisms of microvascular function and dysfunction.1–3 Vascular dysfunction (including impaired endothelium-dependent vasodilation) induced by different pathologies is evident in the cutaneous circulation.4–7 It has been suggested that the skin microcirculation may mirror generalized systemic vascular dysfunction in magnitude and underlying mechanisms.1 Furthermore, minimally invasive skin-specific methodologies using laser systems make the cutaneous circulation a useful translational model for investigating mechanisms of skin physiology and skin pathophysiology induced either by skin disease itself or by other diseases such as vascular, rheumatologic, and pneumologic. To date, the skin has been used as a circulation model to investigate vascular mechanisms in a variety of diseased states, including hypercholesterolemia,8 Alzheimer disease,9 carpal tunnel syndrome,10 schizophrenia,11 hypertension,6 renal disease,12 type 2 diabetes,13 peripheral vascular disease,14 atherosclerotic coronary artery disease,2 heart failure,15 systemic sclerosis,16 obesity,17 primary aging,18,19 and sleep apnea.20 Assessment of skin microvascular function can be done by both invasive and noninvasive techniques. Among noninvasive techniques, laser systems are mainly used.21 The recent development of the laser speckle contrast imaging (LSCI) technique for monitoring skin microvascular function enables its use as a surrogate end point in clinical trials. LSCI allows for noncontact, real-time, and noninvasive monitoring of cutaneous blood flow changes.22,23 Recent evidence has shown that the LSCI technique dramatically reduces the variability of clinical measurements compared with laser Doppler flowmetry (LDF), making the technique a fascinating tool to facilitate microvascular studies in clinical routine.23,24 In this review, we describe …

Noninvasive assessment of endothelial function in the skin microcirculation.

BACKGROUND The structure and function of blood vessels varies along the vascular tree. Endothelial dysfunction is a hallmark of increased cardiovascular (CV) risk that can be assessed by several methods, some of which are invasive and of restricted application. The aim of this study was to determine whether the laser Doppler response of skin microcirculation to acetylcholine, reflects that of conduit artery assessed by brachial artery flow-mediated dilation (FMD). METHODS Noninvasive measurement of endothelium-dependent vasodilation in the skin microcirculation by laser Doppler flowmetry (LDF) in response to a local transdermal iontophoretic application of acetylcholine (Ach-SkBF) is an operator-independent method. Ach-SkBF and FMD were measured in the nondominant upper limb of 55 unselected consecutive patients admitted in our department for evaluation of CV risk factors. RESULTS Ach-SkBF was (mean +/- s.d. (min-max)) 490 +/- 414%, (10-1667%) and FMD was 3.77 +/- 3.01% (0.91-10.91). A strong linear relationship was found between Ach-SkBF and FMD: Ach-SkBF = 122.7 FMD + 25.8 (r = 0.92, P < 0.0001). CONCLUSIONS Endothelial dilatory response to increased blood flow and to acetylcholine are similar in large arteries and in the skin microvasculature. Thus, measurement of blood flow changes in the skin microcirculation using LDF coupled with acetylcholine iontophoresis represents a technically challenging and reliable noninvasive method for the assessment of endothelial function within a large range of normal and altered endothelium responses.

Programming Optimal Atrioventricular Delay in Dual Chamber Pacing Using Peak Endocardial Acceleration: Comparison with a Standard Echocardiographic Procedure

DUPUIS, J.‐M., et al .: Programming Optimal Atrioventricular Delay in Dual Chamber Pacing Using Peak Endocardial Acceleration: Comparison with a Standard Echocardiographic Procedure. Optimization of programmed atrioventricular delay in dual chamber pacing is essential to the hemodynamic efficiency of the heart. Automatic AV delay optimization in an implanted pacemaker is highly desirable. Variations of peak endocardial acceleration (PEA) with AV delay at rest correlate well with echocardiography derived observations, particularly with end‐diastolic filling and mitral valve closure timings. This suggests the possibility of devising a procedure for the automatic determination of the optimal AV delay. The aim of this study was to compare a proposed algorithm for optimal AV delay determination with an accepted echocardiographic method. Fifteen patients with high degree AV block received BEST‐Living pacing systems. Automatic AV delay scans were performed at rest (60–300 ms in 20‐ms steps with 60 beats per step) in DDD at 90 ppm, while simultaneously recording cycle‐by‐cycle PEA values, which were averaged for each AV delay to obtain a PEA versus AV delay curve. Nonlinear regression analysis based on a Boltzmann sigmoid curve was performed, and the optimal AV delay (OAVD) was chosen as the sigmoid inflection point of the regression curve. The OAVD was also evaluated for each patient using the Ritter echocardiographic method. Good sigmoid fit was obtained in 13 of 15 patients. The mean OAVD obtained by the PEA sigmoid algorithm was 146.9 ± 32.1  ms , and the corresponding result obtained by echocardiography was 156.4 ± 34.3  ms (range 31.8–39.7 ms). Correlation analysis yielded r = 0.79, P = 0.0012. In conclusion, OAVD estimates obtained by PEA analysis during automatic AV delay scanning are consistent with those obtained by echocardiography. The proposed algorithm can be used for automatic OAVD determination in an implanted pacemaker pulse generator. (PACE 2003; 26:[Pt. II]:210–213)

Echography of external iliac artery endofibrosis in cyclists

Forty-eight cyclists were studied for suspected external iliac artery endofibrosis with ultrasound B-mode imag ing. In highly trained competition cyclists, symptoms of external iliac artery endofibrosis were characterized by lower limb claudication during maximal effort that was caused by fibrosis thickening of the intima of the exter nal iliac arterial wall. Typical ultrasound imaging aspects consisted of parietal thickening, enhanced echogenicity of the arterial wall, straightness of the abnormal arterial segment, and mild narrowing of the arterial diameter of the proximal or medial segment of the diseased external iliac artery. Although ultrasound B-mode imaging study seems to be useful in the diagnosis of external iliac artery endofibrosis, results with this technique must be compared with results of clinical examination, physio logic tests, and arteriography.

Lower Extremity Arterial Disease in Sports

The recent description of exercise-induced intimal fi brosis affecting mainly the iliac artery (and therefore usually described as external iliac artery endofibrosis) has dramatically changed the diagnostic approach of unexplained recurrent lower limb exercise pain, espe cially in cyclists. Because arterial disease is often as sociated with the aftereffect of various concomitant musculotendinous lesions, several months may pass before an arterial origin is suspected. The arterial origin of the pain must not be eliminated on normal ankle-to- arm index or normal Doppler velocity profiles at rest. Ultrasound examinations taken at rest may show the lesions in 80% of endofibrotic patients and allow for the diagnosis of popliteal entrapment syndrome during dorsiflexion of the foot. However, the hemodynamic consequences of a stenosis on the aortoiliofemoral axis can only be proved by measurement of the ankle- to-arm index after exercise. A cutoff of this index <0.5 provides an 85% sensitivity in the detection of endofi brosis. Invasive investigations (arteriography or an gioscopy) will confirm the diagnosis before surgery is discussed. Although long-term results in endofibrosis are unknown, most of the surgically treated patients return to competition.

The molecular and physiological roles of ABCC6: more than meets the eye.

Abnormal mineralization occurs in the context of several common conditions, including advanced age, diabetes, hypercholesterolemia, chronic renal failure, and certain genetic conditions. Metabolic, mechanical, infectious, and inflammatory injuries promote ectopic mineralization through overlapping yet distinct molecular mechanisms of initiation and progression. The ABCC6 protein is an ATP-dependent transporter primarily found in the plasma membrane of hepatocytes. ABCC6 exports unknown substrates from the liver presumably for systemic circulation. ABCC6 deficiency is the primary cause for chronic and acute forms of ectopic mineralization described in diseases such as pseudoxanthoma elasticum (PXE), β-thalassemia, and generalized arterial calcification of infancy (GACI) in humans and dystrophic cardiac calcification (DCC) in mice. These pathologies are characterized by mineralization of cardiovascular, ocular, and dermal tissues. PXE and to an extent GACI are caused by inactivating ABCC6 mutations, whereas the mineralization associated with β-thalassemia patients derives from a liver-specific change in ABCC6 expression. DCC is an acquired phenotype resulting from cardiovascular insults (ischemic injury or hyperlipidemia) and secondary to ABCC6 insufficiency. Abcc6-deficient mice develop ectopic calcifications similar to both the human PXE and mouse DCC phenotypes. The precise molecular and cellular mechanism linking deficient hepatic ABCC6 function to distal ectopic mineral deposition is not understood and has captured the attention of many research groups. Our previously published work along with that of others show that ABCC6 influences other modulators of calcification and that it plays a much greater physiological role than originally thought.

Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum

OBJECTIVES Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and calcification in the cutaneous, ophthalmologic, and vascular tissues. Cardiovascular manifestations such as peripheral arterial disease (PAD) are frequent in PXE. Because of the changes in the elastic properties and medial calcification of the arterial wall in PXE, the impact of the arterial remodeling on the ankle brachial index (ABI), a well-established diagnostic method for the detection and follow-up of PAD, remains to be determined in this disease. METHODS This was a cross-sectional, comparative, open study, which took place at the PXE Consultation Center, University Hospital of Angers. The subjects were 53 patients (mean age, 49 ± 14 years; 35 females) with PXE clinically proven on the basis of established criteria (skin changes, angioid streaks, and skin biopsy). The ABI at rest, symptoms of intermittent claudication (IC), carotid intima-media thickness (IMT), carotid-femoral pulse wave velocity (c-f PWV), compliance (CC), and β stiffness index were measured in a single-center cohort. RESULTS Forty-five percent of the PXE patients had an ABI ≤0.90, but only one patient had an ABI >1.40. IC was found in 23% of the patients with an ABI ≤0.90. There were no significant differences between the patients with a low and normal ABI in terms of IMT (P = .566) or β stiffness index (P = .194), but differences were significant for c-f PWV (P = .010) and CC (P = .011). Adjusted multivariate linear regression for the Framingham-Laurier score showed that patients with a low ABI had less compliant carotid arteries (B = 0.318, P = .039). CONCLUSIONS PAD detected by a low ABI is very frequent in PXE, although with limited prevalence of symptomatic claudication. Unexpectedly, ABI was low in such calcifying PAD and associated with lower CC, independently of atherosclerosis risk factors. These findings demonstrate that PXE represents a unique monogenic model of PAD in which the specific arterial wall remodeling could change the diagnostic value of the ABI to detect PAD.

Comparison between isoproterenol and nitroglycerin sensitized head-upright tilt in patients with unexplained syncope and negative or positive passive head-up tilt response☆

It is unknown if the head-upright tilt test in patients who receive isoproterenol and nitroglycerin can identify different populations with vasovagal syncope. The aim of this study was to compare the positive or negative responses to passive tilt between isoproterenol- and nitroglycerin-sensitized upright tilt. Ninety-six patients referred for unexplained recurrent syncope underwent passive tilt (45 minutes at 70 degrees angle), which was then systematically followed, within the same session and in a random order, by a 20-minute tilt at a 70 degrees angle after administration of nitroglycerin (NTG-tilt) and 10-minute tilt at a 70 degrees angle with a continuous infusion of isoproterenol (ISO-tilt). NTG-tilt led to significantly more positive responses than passive tilt or ISO-tilt (55% vs 34% vs 42%, respectively). In the subgroup of patients with a positive response during passive tilt, the percentage of positive responses with NTG-tilt was significantly higher than with ISO-tilt (94% vs 67%). The agreement between NTG-tilt and ISO-tilt was very weak (Kappa coefficient 0.06). In the subgroup of patients with a negative response during passive tilt, the percentage of positive responses between NTG-tilt and ISO-tilt was similar (35% vs 29%). The agreement between NTG-tilt and ISO-tilt was good (Kappa coefficient 0.34). NTG-tilt led to a higher number of positive responses than ISO-tilt, especially when passive tilt outcome was positive. These 2 pharmacologic agents may identify 2 different subpopulations of patients because of their specific pharmacologic actions.

Variability and short-term determinants of walking capacity in patients with intermittent claudication

OBJECTIVE Global positioning system (GPS) recordings can provide valid information on walking capacity in patients with peripheral arterial disease (PAD) and intermittent claudication (IC) during community-based outdoor walking. This study used GPS to determine the variability of the free-living walking distance between two stops (WDBS), induced by lower-limb pain, which may exist within a single stroll in PAD patients with IC and the potential associated parameters obtained from GPS analysis. METHODS This cross-sectional study of 57 PAD patients with IC was conducted in a university hospital. The intervention was a 1-hour free-living walking in a flat public park with GPS recording at 0.5 Hz. GPS-computed parameters for each patient were WDBS, previous stop duration (PSD), cumulated time from the beginning of the stroll, and average walking speed for each walking bout. The coefficient of variation of each parameter was calculated for patients with the number of walking bouts (N(WB)) >or=5 during their stroll. A multivariate analysis was performed to correlate WDBS with the other parameters. RESULTS Mean (SD) maximal individual WDBS was 1905 (1189) vs 550 (621) meters for patients with N(WB) <5 vs N(WB) >or= 5, respectively (P < .001). In the 36 patients with N(WB) >or= 5, the coefficient of variation for individual WDBS was 43%. Only PSD and cumulated time were statistically associated with WDBS in 16 and 5 patients, respectively. CONCLUSIONS A wide short-term variability of WDBS exists and likely contributes to the difficulties experienced by patients with IC to estimate their maximal walking distance at leisurely pace. Incomplete recovery from a preceding walk, as estimated through PSD, seems to dominantly account for the WDBS in patients with IC.