Alfonso Ramunni

Soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule 1 in sudden hearing loss.

Hypothesis: The aim of the present study was to evaluate the concentration of soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule 1 in patients affected by sudden sensorineural hearing loss (SSHL). Study Design: Prospective study. Setting: Tertiary referral center. Patients: Patients affected by SSHL were evaluated. Inclusion criteria for this study were hearing loss of more than 30 dB hearing level affecting at least 3 contiguous frequencies, normal hearing on the contralateral ear, negative history of hearing loss or ear surgery in the affected ear, and magnetic resonance with gadolinium negative for VIII cranial nerve pathologic findings. Intervention: Circulating levels of soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule (VCAM) 1 were evaluated by means of enzyme-linked immunosorbent assay. Main Outcome Measures: The levels of adhesion molecules in SSHL patients were compared with those of a control group. Results: Intercellular adhesion molecule 1 and VCAM-1 levels in sera of patients with SSHL were significantly higher than those of the matched control subjects (p < 0.001). Statistical analysis did not show significant differences between the 2 groups in terms of the known vascular risk factors such as total and fractionated cholesterol, triglycerides, fibrinogen, erythrocyte sedimentation rate smoking, and diabetes. Conclusion: The results of this study show that in SSHL patients, there is an increased expression of circulating adhesion molecules confirming the existence of an endothelial dysfunction and supporting the vascular involvement in the pathogenesis of the disease. The identification of high levels of adhesion molecules and of the endothelial dysfunction open the way to selective pharmacologic treatments able to correct the activation of endothelial cells.

LDL-Apheresis Accelerates the Recovery of Nonarteritic Acute Anterior Ischemic Optic Neuropathy

Abstract:  Nonarteritic acute anterior ischemic optic neuropathy (NAION) is a disabling disease which impairs visual function. It is presumed to result from disturbances of microcirculation in the anterior portion of the optic nerve head due to hemodynamic factors derived from excessive blood viscosity, or restriction of the vasal lumen in hypertensive, hypercholesterolemic, diabetic patients. We aimed to determine whether acute reduction of plasma fibrinogen and serum low‐density lipoprotein (LDL) cholesterol is effective for treatment of NAION. We recruited 11 patients (7 females, 4 males) with a mean age of 57.2 ± 19.6 years. All except one of them presented risk factors for atherosclerosis. The mean values of LDL‐cholesterol and fibrinogen before treatment were 144 ± 32 mg/dL and 341 ± 80 mg/dL, respectively. All were treated with standard therapy (prednisone, salicylate, pentoxiphyllin) and underwent three sessions of LDL‐apheresis (HELP system—B Braun) that can reduce plasma LDL‐cholesterol and fibrinogen by more than 50% in a very short time. In all patients we observed a drastic reduction of LDL cholesterol and fibrinogen and a clear improvement in the visual functional data. In fact, mean values of corrected vision increased from 3.7/10 ± 3/10 to 7.9/10 ± 2.2/10 (P = 0.002) after the third session, while the scotomatous portion of the visual field regressed after the first session, and in 5 patients further regressed after the third session. This improvement had remained stable after 3 months. Thanks to its effect of antagonizing hemorheologic disorders of the ocular microcirculation, fibrinogen/LDL‐apheresis seems to be an efficacious treatment of NAION.

Does a Reduction of Adhesion Molecules by LDL-Apheresis Have a Role in the Treatment of Sudden Hearing Loss?

Abstract:  Sudden hearing loss (SHL) is a highly disabling affliction that can severely affect the subject’s social and relational life. Although the etiology of the complaint is still debated, it is thought that microcirculation disturbances conditioned by an endothelial dysfunction might be the main pathogenetic mechanism. Adhesion molecules favoring interaction between leukocytes and endothelial cells are early markers of endothelial damage. In the present report, we describe a case of SHL that derived evident benefit from a single session of LDL/fibrinogen apheresis, with complete hearing recovery. In this patient, in addition to reducing LDL cholesterol and fibrinogen, the circulating adhesion molecules (sE‐selectin, sVCAM‐1 and sICAM‐1), previously present in higher than normal concentrations, were reduced by the treatment.

Effect of Low-Density Lipoprotein Apheresis on Circulating Endothelial Progenitor Cells in Familial Hypercholesterolemia

Background: Long-term treatment with low-density lipoprotein (LDL) apheresis (LA) has been shown to reduce the incidence of cardiovascular events in patients affected by familial hypercholesterolemia (FH). Data from experimental studies suggest that circulating endothelial progenitor cells (EPCs) can repair the vascular lesions caused by atherosclerosis. Since a reduction of these cells has been demonstrated to predict atherosclerosis progression, the aim of this study was to verify whether LA can increase the percentage of EPCs. Methods: In 15 patients affected by FH periodically treated with LA, the percentage of EPCs was determined before and after performing LA, and compared with the values of 15 control subjects and 15 hypercholesterolemic patients treated with statins. Results: Significant differences were found in FH patients between the pre-apheresis percentages of CD34+/KDR+, defined as EPCs by a wide consensus of opinion, and the values found 24 h after the procedures (0.00868 ± 0.003 vs. 0.01009 ± 0.002%, p < 0.005). Instead, the percentages of CD34+/KDR+/CD133+, considered as an immature subset of EPCs, remained substantially unchanged. However, a significant reduction in the percentage of EPCs was observed in both patient groups as compared to the controls, at all the assessment times. Conclusion: In the short-term LA seems to stimulate mobilization of CD34+/KDR+ cells. Hypercholesterolemic patients show a lower percentage of EPCs than controls. There were no differences in the EPCs percentages between the 2 patients groups, despite the fact that LDL cholesterol levels were higher in the group undergoing LA.

Endothelial progenitor cells in sudden sensorineural hearing loss.

Abstract Conclusions: Endothelial progenitor cells (EPCs) are a unique subtype of circulating cells with properties similar to those of embryonal angioblasts. They have the potential to proliferate and to differentiate into mature endothelial cells. EPCs are reduced in patients with vascular risk factors due to a decreased mobilization, an increased consumption at the site of damage or a reduced half-life. The results of this study confirm the existence of an endothelial dysfunction in patients with sudden sensorineural hearing loss (SSHL) and support the vascular involvement in the pathogenesis of the disease. Objective: The aim of this study was to evaluate the concentration of EPCs in patients affected by SSHL. Methods: Twenty-one patients affected by SSHL were evaluated. The number of EPCs was analyzed by flow cytometry analysis of peripheral blood CD34+KDR+CD133+ cells. Results: Circulating levels of EPCs were significantly lower in SSHL patients compared with controls. In particular, CD34+KDR+ cells and CD34+CD133+KDR+ cells were significantly reduced (p < 0.05).

Pleiotropic effects of LDL apheresis.

LDL apheresis (LA), a technique employed to remove atherogenic lipoproteins, has been shown to exert a protective function on the vessel walls. This effect can be attributed to pleiotropic mechanisms that safeguard against endothelial dysfunction by reducing the concentrations of pro-inflammatory and pro-coagulation markers. Besides these actions, LA improves whole blood viscosity and endothelium-mediated vasodilation, and has a positive effect on the hemorheological picture, improving perfusion in the microcirculation. Although the short term effects on the functional component of the vascular damage seem to be temporary, long term effects on the morphological alterations have also been shown. It is still not clear which of the many proposed actions, or others still to be discovered, is the principal vessel protective mechanism.

Fibrinogen Apheresis in the Treatment of Peripheral Arterial Disease

Background: Fibrinogen is mainly responsible for determining the viscosity of whole blood. In peripheral arterial disease (PAD) the fibrinogen concentration seems to affect the microcirculation flow. Aim: To study the effects of an abrupt reduction of fibrinogen on the hemodynamics of the lower extremities and the clinical picture of patients with PAD. Methods: Ten patients affected by various stages of PAD underwent 1 session of fibrinogen apheresis (TheraSorb, Miltenyi Biotec, Germany). Laboratory parameters of endothelial activation were assessed before and after the session, as well as walking distance (WD), the ankle-brachial index and laser Doppler flowmetry. Results: A significant reduction in the laboratory parameters was observed: fibrinogen (50%), total cholesterol (18%), LDL cholesterol (24%), sE-selectin (23%), sICAM-1 (19%) and sVCAM-1 (10%). The procoagulant factors, factor VIII and von Willebrand factor, did not vary significantly. Both pain-free and total WD were significantly improved (p < 0.003 and p <0.006, respectively), the ankle-brachial index remained unchanged, and laser Doppler flowmetry showed a modest but not significant increase. Conclusions: Fibrinogen apheresis allowed us to study the effects of an acute modification of fibrinogen in PAD, on both some aspects of the endothelial function and on the hemodynamics, demonstrating an improvement of WD and a minimal increase in the skin microcirculation.

A Case Report of Double Filtration Plasmapheresis in an Acute Episode of Multiple Sclerosis

Abstract:  Plasma exchange has been proposed as support therapy in both acute and chronic forms of multiple sclerosis (MS). For the first time, we aimed to assess whether double filtration plasmapheresis (DFPP) could be clinically efficacious. We describe the case of a patient affected by MS who developed a severe crisis refractory to conventional steroids, and immunosuppressive and immunomodulating therapy. The patient underwent 12 sessions of DFPP. In each session 3000 mL of plasma was treated. Before and immediately after each session the routine laboratory parameters were assessed. Before the apheresis cycle and one month after the end of treatment, encephalic magnetic resonance imaging (MRI) was performed. A neurological examination and assessment of the extended disability status scale (EDSS) were made once each week from the beginning of treatment until one month after the end of the cycle. No therapy was administered during the course of the apheresis cycle, with the exception of a scaled dose of steroids, that was completely withdrawn half‐way through the cycle. The immunoglobulin (Ig) G, IgA and IgM values declined from 465 ± 104 mg/dL, 69 ± 18 mg/dL, 34 ± 16 mg/dL, respectively, pre‐apheresis to 331 ± 76 mg/dL, 42 ± 5 mg/dL, 15 ± 6 mg/dL, respectively, post‐apheresis; C3 and C4 decreased from 105 ± 27 mg/dL and 21 ± 5 mg/dL to 75 ± 9 mg/dL and 15 ± 4 mg/dL, respectively; fibrinogen went from 228 ± 72 mg/dL to 128 ± 28 mg/dL. The EDSS dropped from a value of 6 before the cycle to 5.5 one month after the end of the treatment. As compared with the pretreatment conditions, post‐apheresis MRI showed stabilization of the lesions already present, the reduction of one lesion and a complete absence of enhancement of all lesions. DFPP, adopted for the first time in MS, seems to foster a short‐term improvement in both the clinical and magnetic resonance images during an acute MS episode.

Cutaneous Microcirculation Is Impaired in Early Autosomal Dominant Polycystic Kidney Disease

Background/Aims: An endothelial dysfunction has been described in autosomal dominant polycystic kidney disease (ADPKD) before the development of hypertension and renal impairment. The aim of this work was to verify the existence of a microvascular reactivity in the early stages of ADPKD. Methods: Fifteen ADPKD normotensive patients with normal renal function underwent laser Doppler examination of the cutaneous microcirculation in basal conditions and after the warm test, as well as evaluation of plasma concentrations of some endothelial activation parameters [total cholesterol and fractions, fibrinogen, von Willebrand factor, Lp(a)]. The results were compared with those in 15 healthy subjects, 15 essential hypertensive patients and 15 hypertensive ADPKD patients with normal renal function. Results: Both basal and post-warm-test values were significantly lower in normotensive ADPKD subjects than controls (3.2 ± 1 vs. 5.8 ± 1.3 AU, p = 0.0001; 35.2 ± 10.9 vs. 50.5 ± 10.8 AU, p = 0.005, respectively). All evaluated parameters were within normal limits and comparable between normotensive ADPKD subjects and controls, except for LDL cholesterol (125 ± 18 vs. 101 ± 22 mg/dl, p = 0.01) and Lp(a), which was significantly higher in the ADPKD subjects (52.2 ± 36 vs. 6.0 ±4 mg/dl, p = 0.0006). Conclusion: Our study confirms the existence of a systemic microcirculation defect in ADPKD. The presence of high levels of Lp(a) could contribute to causing the high incidence of cardiovascular events in ADPKD.

Double Filtration Plasmapheresis: An Effective Treatment of Cryoglobulinemia

In cryoglobulinemic vasculitis, circulating immune complexes are deposited intravascularly, resulting in organ damage. Removal of these aggressive agents by means of therapeutic apheresis procedures improves the clinical status. Until recently, plasma exchange was the treatment of choice but the advent of selective methods has provided more versatile tools. Double filtration plasmapheresis (DFPP) can eliminate high-molecular-weight substances, mainly immunoglobulins and lipoproteins, while sparing the remainder of the plasma, which can then be restored to the patient without the need to infuse replacement solutions. This semi-selective method has been successfully employed to treat skin lesions caused by cryoglobulinemic vasculitis resistant to traditional therapy. By eliminating precipitating cryoglobulins, DFPP targets the pathogenic component of the vascular damage. Moreover, since it also removes hepatitis C virus particles, known to be the main cause of cryoglobulinemia, it is able to reduce the impact of the etiological agent of the vasculitis. Although DFPP has been regarded as a salvage therapeutic option for use in emergencies and confined to cases refractory to standard medical therapy, its role as an integrated, synergistic form of treatment should now be recognized.