Microvascular Density and Circulating Endothelial Progenitor Cells Before and After Treatment with Incretin Mimetics in Diabetic Patients.

INTRODUCTION: Glucagon-like peptide 1-receptor agonists (incretin mimetics) and dipeptidyl peptidase-4 inhibitors (incretin enhancers) have been recently introduced in the treatment of diabetes mellitus. In particular, incretin mimetics seems to have ancillary antioxidant/antinflammatory properties that might be involved in endothelial protection. AIM: To investigate the effect of incretin mimetic therapy (liraglutide, exenatide) given to 11 patients with type 2 diabetes mellitus, on circulating endothelial progenitor cells (EPCs) (bone marrow-derived cells possibly participating in neovascularization and endothelial protection and repair) and capillary density. METHODS: Four diabetic patients were treated with exenatide (5 µg twice daily for 4 weeks and then 10 µg twice daily for 3 weeks) and 7 with liraglutide (0.6 mg per day for 1 week and then 1.2 mg per day for 3 weeks). Peripheral venous blood samples were obtained before treatment (basal) and after 4 week in patients treated with liraglutide, and after 4 and 7 weeks in patients treated with exenatide, since drug titration is usually longer. EPCs were evaluated by flow cytometry as CD34+/KDR+ cells. Capillary density was evaluated by videomicroscopy, before and after venous congestion, in the dorsum of the 4th finger. RESULTS: Patients treated with liraglutide (6 males 1 female, age 54 ± 12 years) showed a decrease in body mass index and blood pressure during treatment, while patients treated with exenatide (3 males 1 female, age 57 ± 6 years) did not show any relevant change. EPCs were significantly increased after treatment with exenatide, but not after treatment with liraglutide. Capillary density was slightly increased only after 4 weeks of treatment with exenatide, however the increase was no longer present at the final evaluation. CONCLUSIONS: Treatment with exenatide, but not with liraglutide, was able to increase the number of circulating EPCs, possibly through an antioxidative/antiinflammatory effect.

Management of VEGF-Targeted Therapy-Induced Hypertension.

PURPOSE OF REVIEW: From a physiological point of view, VEGFs (vascular endothelial growth factors) and their receptors (VEGFR) play a critical role in vascular development angiogenesis, endothelial function, and vascular tone. On the pathological side, VEGF-VEGFR signaling may induce dysregulated angiogenesis, which contributes to the growth and to the spread of tumors, being essential for neoplastic proliferation and invasion. RECENT FINDINGS: Pharmacological inhibition of VEGF-VEGFR is now a cornerstone in the treatment of many malignancies; however, treatment with VEGF inhibitors is commonly associated with an increase in blood pressure values. This side effect is strictly connected with the mechanism of action of these medications and might represent an index of therapy efficacy. The optimal management of this form of hypertension is, at present, not clear. Calcium channel blockers and renin-angiotensin system inhibitors probably represent the most appropriate classes of hypertensive dugs for the treatment of this condition; however, no conclusive data are presently available.

Decreased circulating T regulatory lymphocytes in obese patients undergoing bariatric surgery.

OBJECTIVE: It has been previously demonstrated that T lymphocytes may be involved in the development of hypertension and microvascular remodeling, and that circulating T effector lymphocytes may be increased in hypertension. In particular, Th1 and Th 17 lymphocytes may contribute to the progression of hypertension and microvascular damage while T-regulatory (Treg) lymphocytes seem to be protective in this regard. However, no data is available about patients with severe obesity, in which pronounced microvascular alterations were observed. DESIGN AND METHODS: We have investigated 32 severely obese patients undergoing bariatric surgery, as well as 24 normotensive lean subjects and 12 hypertensive lean subjects undergoing an elective surgical intervention. A peripheral blood sample was obtained before surgery for assessment of CD4+ T lymphocyte subpopulations. Lymphocyte phenotype was evaluated by flow cytometry in order to assess T-effector and Treg lymphocytes. RESULTS: A marked reduction of several Treg subpopulations was observed in obese patients compared with controls, together with an increased in CD4+ effector memory T-effector cells. CONCLUSION: In severely obese patients, Treg lymphocytes are clearly reduced and CD4+ effector memory cells are increased. It may be hypothesized that they might contribute to the development of marked microvascular alterations previously observed in these patients.

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.

Comparison of lercanidipine plus hydrochlorothiazide vs. lercanidipine plus enalapril on micro and macrocirculation in patients with mild essential hypertension.

Dihydropyridine calcium channel blockers may possess antioxidant properties, and might improve micro and macrovascular structure and function. Combination treatment with an ACE inhibitor may have additional advantages, compared with a thiazide diuretic. The aim of the present study is to investigate the effects of a short-term treatment with lercanidipine, and to compare two combination treatments: lercanidipine + enalapril vs. lercanidipine + hydrochlorothiazide on structural alterations in retinal arterioles, on skin capillary density and on large artery distensibility. Thirty essential hypertension patients are included in the study, and treated for 4 weeks with lercanidipine 20 mg per day orally. Then, they were treated for 6 months with lercanidipine + enalapril (n = 15) or lercanidipine + hydrochlorothiazide (n = 15) combinations. Investigations were performed on basal condition, after appropriate wash out of previous treatments, after 4 weeks of lercanidipine monotherapy treatment, and at the end of the combination treatment. Non-invasive measurements of wall-to-lumen ratio (WLR) and other morphological parameters of retinal arterioles were performed using either scanning laser Doppler flowmetry or adaptive optics. Capillary density was evaluated by capillaroscopy, while pulse wave velocity was measured, and central blood pressures were assessed by pressure waveform analysis. A significant improvement of WLR and other indices of retinal artery structure is observed with both technical approaches after treatment with lercanidipine alone, with a further improvement after treatment with lercanidipine + enalapril, while after treatment with lercanidipine + hydrochlorothiazide, the improvement is partially blunted. Central systolic and diastolic blood pressures are similarly reduced by both therapeutic strategies. Capillary density is increased only after treatment with lercanidipine + enalapril. In conclusion, lercanidipine both in monotherapy and in combination with enalapril but not with hydrochlorothiazide is able to improve microvascular structure; on the other hand, a decrease in central blood pressure is observed with both therapeutic combinations.