Growth Hormone, Atherosclerosis and Peripheral Arterial Disease: Exploring the Spectrum from Acromegaly to Growth Hormone Deficiency.

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are increasingly recognised for their role in cardiovascular (CV) physiology. The GH-IGF-1 axis plays an essential role in the development of the CV system as well as in the complex molecular network that regulates cardiac and endothelial structure and function. A considerable correlation between GH levels and CV mortality exists even among individuals in the general population without a notable deviation in the GHIGF- 1 axis functioning. In addition, over the last decades, evidence has demonstrated that pathologic conditions involving the GH-IGF-1 axis, as seen in GH excess to GH deficiency, are associated with an increased risk for CV morbidity and mortality. A significant part of that risk can be attributed to several accompanying comorbidities. In both conditions, disease control is associated with a consistent improvement of CV risk factors, reduction of CV mortality, and achievement of standardised mortality ratio similar to that of the general population. Data on the prevalence of peripheral arterial disease in patients with acromegaly or growth hormone deficiency and the effects of GH and IGF-1 levels on the disease progression is limited. In this review, we will consider the pivotal role of the GH-IGF-1 axis on CV system function, as well as the far-reaching consequences that arise when disorders within this axis occur, particularly in relation to the atherosclerosis process.

Endocrine Disorders and Peripheral Arterial Disease - A Series of Reviews Cushing Syndrome-Cortisol Excess.

Cushing syndrome (CS), characterised by endogenous or exogenous glucocorticoid hormone excess, is associated with several systemic complications, including impaired glucose metabolism, which often becomes clinically manifest as diabetes mellitus (DM). In addition, CS can harm the arterial wall because of hyperglycaemia, dyslipidaemia, hepatic steatosis, and central obesity. These metabolic disorders promote atherosclerosis by synthesising adipokines, leptin, and proinflammatory cytokines. Lower limb arterial complications in CS are common and significantly impact morbidity and mortality. Furthermore, CS, in combination with DM, is likely to cause more diffuse vascular disease that predominantly affects distal arterial beds. In conclusion, CS promotes atherosclerosis, including peripheral artery disease, by causing functional and morphological deterioration of the arterial vessel wall and increasing the presence of classical risk factors of atherosclerosis.

[The influence of Cytoflavin therapy on the cerebral hemodynamics in patients with various stages of hypertensive disease]. / Vliianie terapii preparatom tsitoflavin na sostoianie tserebral'noi gemodinamiki pri razlichnykh stadiiakh gipertonicheskoi bolezni.

AIM: To study an influence of cytoflavin therapy on the cerebral hemodynamics in patients with various stages of hypertensive disease (HD). MATERIAL AND METHODS: One hundred and forty patients with HD, I-III stages, were randomized into 2 groups: patients of group 1 received complex treatment (antihypertensive therapy and cytoflavin), patients of group 2 were treated with antihypertensive therapy. The control group consisted of 30 healthy people. The changes in cerebral hemodynamics using the algorithm of the complex ultrasound study of cerebral vascular system were assessed. RESULTS: Disturbances of hemodynamics at all structural/functional levels of cerebral vascular system were found in all HD stages. There were a decrease in the blood flow through the common carotid, inner carotid, spinal and middle cerebral arteries, reactivity of veins of Rosenthal, blood flow through veins of Rosenthal and inner jugular veins and an increase of blood flow through spinal veins. The hemodynamic study showed that in group 1 there was the increase of blood flow through common carotid, inner carotid, middle cerebral arteries in stage I and through spinal arteries in stage I-II of HD; improvement of the reactivity of veins of Rosenthal, restoration of blood flow parameters through the veins of Rosenthal and inner jugular veins to control values, the decrease in blood flow velocity through the spinal veins in all HD stages. CONCLUSION: HD is accompanied by the damage of all structural/functional levels of cerebral vascular system. The use of cytoflavin in the complex therapy of HD exerts a positive influence on the cerebral hemodynamics reducing the severity of arterial insufficiency in the initial stages of disease, improving microcirculation and venous hemodynamics in all HD stages.

Flow-mediated dilation benefits of mesoglycan in peripheral artery disease.

AIM: Mesoglycan, composed of natural glycosaminoglycans, is used for treatment in arterial and venous disease for its benefits on endothelial glicocalix. Little is known about mesoglycan impact on endothelial blood flow regulation. We sought to evaluate the effects of mesoglycan intermittently added to back-ground treatments on impairment of endothelial function in peripheral arterial disease (PAD) patients. METHODS: We studied the effects of a 2+2 months oral treatment with 50 mg b.i.d. of mesoglycan, intervalled by 2 months without mesoglycan, in 540 PAD patients on four occasions (visit 1: baseline, visit 2: 2 months, visit 3: 4 months and visit 4: 6 months). At these time visits we assessed brachial artery endothelial-dependent flow-mediated dilation (FMD), together with femoral intima-medial thickness (IMT), and walking distance (WD). RESULTS: There were significant changes in FMD (1.88%, CI 95%: 1.13, 2.63; P<0.001), IMT (-0.05 mm, CI 95%: -0.07,-0.02; P<0.001) and WD (38,9%, CI 95% 33.2, 44.8; P<0.001). The positive effects and benefit were maintained during the two-months interval without mesoglycan treatment. Significant changes in FMD were observed in a number of patient groups, stratified for risk factors (aging, sex, smoke, diabetes, dyslipidemia, hypertension). CONCLUSION: Two months cycles with mesoglycan improved endothelial function in PAD patients, with a parallel reduction of atherosclerotic damage and amelioration of clinical condition.

Renal Stenting for Kidney Salvage in the Management of Renal Artery Atherosclerotic Stenosis.

We studied the usefulness of preoperative resistance index to select patients who will benefit most from renal stenting. Sixty-two patients underwent renal stenting. All had chronic renal insufficiency with serum creatinine values ranging from 1.5 to 2.5 mg/dL and blood urea nitrogen between 80 and 107 mg/dL. All treated renal artery stenosis were >70%. Reduction in blood pressure in the early stages was observed in 39 (62.9%) patients; 31 (79.4%) patients returned to preoperative values within 12 months. A progressive reduction in creatinine values and blood urea nitrogen was reached in 43 (69.4%) patients, 12 (19.4%) patients remained unchanged, and the remaining 7 (11.2%) patients worsened. The best improvement in renal function was obtained in patients with a resistance index of ≤0.75 A preoperative resistance index up to 0.75 could be used as an indicator to predict which candidates will have improved renal function after stenting.

Medical management of patients with peripheral arterial disease.

Peripheral arterial disease (PAD) is one of the most frequent manifestations of atherosclerosis and is associated with atherosclerosis in the coronary and carotid arteries, leading to a highly increased incidence of cardiovascular events. Major risk factors of PAD are similar to those that lead to atherosclerosis in other vascular beds. However, there are differences in the power of individual risk factors in the different vascular territories. Cigarette smoking and diabetes mellitus represent the greatest risks of PAD. For prevention of the progression of PAD and accompanying cardiovascular events similar preventative measures are used as in coronary artery disease (CAD). However, recent data indicate that there are some differences in the efficacy of drugs used in the prevention of atherothrombotic events in PAD. Antiplatelet treatment is indicated in virtually all patients with PAD. In spite of the absence of hard evidence- based data on the long term efficacy of aspirin, it is still considered as a first line treatment and clopidogrel as an effective alternative. The new antiplatelet drugs ticagrelol and prasugrel also represent promising options for treatment of PAD. Statin therapy is indicated to achieve the target low density lipoprotein cholesterol level of ≤2.5 mmol/L (100 mg/dL) and there is emerging evidence that lower levels are more effective. Statins may also improve walking capacity. Antihypertensive treatment is indicated to achieve the goal blood pressure (<140/90 mmHg). All classes of antihypertensive drugs including beta-blockers are acceptable for treatment of hypertension in patients with PAD. Diabetic patients with PAD should reduce their glycosylated haemoglobin to ≤7%. As PAD patients represent the group with the highest risk of atherothrombotic events, these patients need the most intensive treatment and elimination of risk factors of atherosclerosis. These measures should be as comprehensive as those in patients with established coronary and cerebrovascular disease.

Consensus Document on Intermittent Claudication from the Central European Vascular Forum (C.E.V.F.)-3rd revision (2013) with the sharing of the Mediterranean League of Angiology and Vascular Surgery, and the North Africa and Middle East Chapter of International Union of Angiology.

This paper is the review of the Consensus Document on Intermittent Claudication of the Central European Vascular Forum (CEVF), published in 2008, and and shared with the North Africa and Middle East Chapter of International Union of Angiology and the Mediterranean League of Angiology and Vascular Surgery. The Document presents suggestions for general practitioners and vascular specialists for more precise and appropriate management of PAD, particularly of intermittent claudication, and underlines the investigations that should be required by GPs and what the GP should expect from the vascular specialist (angiologist, vascular surgeon). The idea of the Faculty is to produce a short document, which is an easy reference in daily clinical practice, both for the GPs and vascular specialists.

Acceptance, compliance and effects of compression stockings on venous functional symptoms and quality of life of Italian pregnant women.

AIM: The rates of pregnant women with functional symptoms of venous insufficiency who accepted or refused to wear therapeutic compression stockings were evaluated and compared in relation to their clinical evolution and their compliance levels. METHODS: The observational study was conducted in pregnant women between 4 and 28 weeks of amenorrhea presenting a CEAP C0S to C3S venous disease. Therapeutic compression stockings (BSN medical, UltraSheer Maternity stockings, 15-20 mmHg) were offered to pregnant women satisfying the inclusion criteria during routine check visits, and both groups of patients (those who accepted as well as those who refused) were followed up until the end of the pregnancy. The clinical profiles of both groups and the evolution of the venous insufficiency were monitored and compared. The women were requested to indicate pain and further quality of life parameter by means of a specific questionnaire (CIVIQ). RESULTS: Ninety-eight women were included in the study and followed up; 30.6% (N.=30) of the women refused to wear compression stockings (Wr), 69.4% accepted 10.6% were not compliant to a daily wear (Wanc) and 58.8% wore them every day (Wac). Leg pain was more prominent in case of the Wac group (49.5 ± 21.3) than in case of the Wanc (42.1 ± 20.4) and Wr groups (36.6 ± 18). Their global quality also decreased (48.8 ± 15.7 vs. 43.6 ± 16.1 and 36.6 ± 15.6). Regular use of compression stockings led to decrease of pain (Wac -17 ± 10.1 vs. Wanc -10.3 ± 10.5 vs. Wr -4.2 ± 9.8 [P < 0.0001]) and enhanced total quality of life (Wac 13.5 ± 9.6 vs. Wanc 10.7 ± 11.3 vs. Wr -3.3 ± 9.4 [P < 0.0001). Similar results were observed on the CIVIQ subscale (pain, psychological, social, physical impact of legs' pain on women quality of life). CONCLUSION: In daily practice, more than two third of the pregnant women accepted to wear compression stockings. The use of compression stockings reduced the legs pain and increased the quality of life of pregnant women.

Update on distal deep venous thrombosis. Reports of a multicenter study.

AIM: No study of strong methodology could be found to resolve the controversy of optimal treatment of distal deep venous thrombosis (DDVT). Some inconclusive evidence exists on two approaches to care: anticoagulants and compression therapy or compression therapy and Duplex scanning monitoring. Different studies report propagation to popliteal vein in 8% of patients without anticoagulant treatment, while a complete thrombus resolution within 4 weeks occurred in 20% of patients. We report data of a study conducted in patients affected by DDVT and treated with nadroparin administered once daily in association with compression therapy. METHODS: One hundred and ten patients with DDVT of the gastrocnemius or tibial veins, assessed by Duplex scanning, were enrolled in 8 clinical centres of the Lazio Region. At baseline, patient demographics, medical history (including risk factors for DDVT), circumferences of both calves and ankles, and a VAS-pain scale were recorded. At 7 and 28 days from baseline, patients were re-assessed by Duplex scanning, calves and ankles circumferences and VAS-pain were measured, and the patients were asked about possible side effects. RESULTS: At the end of the study period, no propagation to the popliteal vein was observed, and no side effects were reported. Overall, the calf circumference in the affected leg significantly decreased from baseline (38.1 cm) to week 1 (37.1 cm), and to week 4 (35.7 cm). Also the VAS-pain scores significantly decreased during the study - the observed means were 58.4, 30.7, and 12.7 at the three visits, respectively. The percentage of partial recanalization of tibial DVT at 7 days was lower than gastrocnemius DVT (31.6% vs. 59.8%) whereas the percentage of total recanalization at 28 days was comparable (52.6% vs. 59.8%). Complete recanalization occurred in 56.4% of all patients. CONCLUSION: Our study suggests that anticoagulant treatment, associated with compression therapy, is safe and causes clinical improvement (as assessed by calf measurements) and pain relief. Overall complete resolution (56.4%) is significantly higher than in untreated patients (20%). Such results, together with the already reported higher satisfaction of patients for the once-daily administration regimen, should be considered as a viable option for the treatment of DDVT.

Quality of live as measured by the CIVQ 20. Questionnaire following oral mesoglycan treatment of patients with chronic venous disease.

AIM: Several studies have demonstrated the effective antithrombotic action of mesoglycan to treat chronic venous disease (CVD). The study aimed to assess clinical and quality of life (QoL) (CIVIQ 20 questionnaire) improvements in mesoglycan-treated patients with clinical, etiological, anatomical and pathophysiological (CEAP) stages 2 and 3. METHODS: The open, multicentre, uncontrolled, observational, prospective study involved treating patients with 50 mg x 2/day mesoglycan for 2 months and measuring improvement to lower-limb edema and QoL in the Global, Physical, Pain, Psychological, and Social Dimensions of the Chronic Venous Disease Quality-of-Life Questionnaire (CIVIQ 20) at the first, baseline visit (V1), at the end of treatment (V2) and 2 (V3) and 4 months after treatment completion (V4). At the last visit (V4), patient disease status was assessed objectively (by the treating physician) and subjectively (by the patient). The study population was divided into three groups: 1) patients with only varicose veins; 2) patients with only lower-limb edema; 3) patients with varicose veins and edema (ITT population). RESULTS: Seventy-five centers enrolled 1066 patients (ITT population); 914 patients completed the study. Mesoglycan treatment produced significant improvement of edema and lower-limb circumference at every visit, in both patients with edema alone and those with edema and varicose veins (paired sample t-test P<0.001). QoL improved significantly in all questionnaire dimensions in all three patient groups even after treatment was concluded (V2). Improvement continued up to the end of the study observation period (V4) (paired sample t-test P<0.001). Objective clinical improvement of the underlying CVD was found in 76.82% of patients with varicose veins alone, in 82.83% of patients with edema alone, and in 76.7% of patients with varicose veins and edema. Patients' own subjective assessment of improvement was 82.0%, 79.39% and 79.39% respectively for the three groups. CONCLUSION: Results showed mesoglycan treatment to improve QoL significantly in patients with CVD as measured by a specific questionnaire like the CIVIQ 20. The extent of average edema reduction observed at the last visit (4 months after the end of drug treatment), suggests mesoglycan might have an etiological role, modifying the physiological factors underlying CVD and not just affording temporary improvement of symptoms.

Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2013.

Primary lymphedema can be managed effectively as a form of chronic lymphedema by a sequenced and targeted treatment and management program based around a combination of Decongestive Lymphatic Therapy (DLT) with compression therapy, when the latter is desired as an adjunct to DLT. Treatment in the maintenance phase should include compression garments, self-management, including self-massage, meticulous personal hygiene and skin care, in addition to lymphtransport-promoting excercises and activities, and, if desired, pneumatic compression therapy applied in the home. When conservative treatment fails, or gives sub-optimal outcomes, the management of primary lymphedema can be improved, where appropriate, with the proper addition of surgical interventions, either reconstructive or ablative. These two surgical therapies can be more effective when fully integrated with manual lymphatic drainage (MLD)-based DLT postoperatively. Compliance with a long-term commitment to MLD/DLT and particularly compression postoperatively is a critical factor in determining the success of any new treatment strategy involving either reconstructive or palliative surgery. The future of management of primary lymphedema has never been brighter with the new prospect of gene-and perhaps stem-cell oriented management.

The CEAP-L classification for lymphedemas of the limbs: the Italian experience.

AIM: A method to classificate lymphedema has been needed to gather all the important information on the clinical evolution of the disease using a common language and an easy clinical applicability. METHODS: The proposal for a new classification of the limb lymphedema was inspired by the C.E.A.P. classification for chronic venous insufficiency of the lower limb. The classification adopts the acronym C.E.A.P. by adding the letter L to underline the aspect ''lymphedema'' and is based on clinical data such as extension of lymphedema, presence of lymphangitis, leg ulcers and loss of functionality of the limb and instrumental criteria that permit to confirm and precise diagnosis. The Clinical classification is based on the most objective sign in these patients, the edema which is subdivided into 5 classes depending on the clinical manifestations. The etiological aspect considers 2 types of alterations of the lymphatic system: congenital and acquired. The anatomic is aimed to locate the anatomical structures involved. Pathophysiological conditions are gathered into 5 groups: agenesia or hypoplasia, hyperplasia, reflux, overload, obstruction. RESULTS: The classification has already been appraised after 4 years of activity at the unit of Vascular and Endovascular Surgery of Ferrara, at the S. Giovanni Battista Hospital in Rome, at the Umberto I Ancona Hospital and at the S. Giovanni-Addolorata Hospital in Rome. CONCLUSIONS: The proposal for a new classification of lymphedema C.E.A.P. L was developed in order to categorize patients with definite and objective marks, creating clinical reports with a common vocabulary, clear to all clinicians, permitting to stage the disease, evaluate treatment and finally obtain epidemiological and statistical data.

Isolated distal deep vein thrombosis: efficacy and safety of a protocol of treatment. Treatment of Isolated Calf Thrombosis (TICT) Study.

AIM: The optimal treatment of isolated distal deep vein thrombosis (ID-DVT) is still controversial. A complete anticoagulation as soon as the diagnosis is made is recommended by some authors. Alternatively, other authors suggest to perform serial ultrasonography assessments to detect the possible extension of DVT towards proximal veins. Only in this case the treatment should be initiated. Furthermore, the optimal duration of treatment is far from established. The Treatment of Isolated Calf Thrombosis (TICT) study was set up to assess the efficacy and safety of a particular treatment regimen of ID-DVT based on low molecular weight heparins (LMWH). METHODS: The drug treatment consisted of a twice-daily subcutaneous administration of a full dose of weight-adjusted LMWH for one week, followed by a half dose of LMWH administered once-daily for another three weeks. At the end of the four-week period of treatment, a colour-coded Doppler ultrasonography (CCDU) assessment was scheduled and after three months a follow-up visit was performed. If a patient was unable to attend the visit, he was contacted by a phone-call to assess if any adverse events occurred. The study enrolled 192 outpatients with ID-DVT confirmed by CCDU. Twenty-one out of 192 patients (10.9%) were excluded for violation of protocol. Thus 171 (39.9% men, mean age of 60.45 years ) were eligible and were included in the study. Sixty-one patients (36.6%) presented an unprovoked ID-DVT. RESULTS: Events during the period of treatment (4 weeks). Ten out of 171 patients (5.8%) had complications: five patients showed an extension proximal to the knee (2.9%) all with an unprovoked ID-DVT; two showed an extension of thrombus within the distal veins. Three patients (1.7%) suffered from minor bleeding; there was no major bleeding. Further events during three months of observation occurred. Five patients had thrombus recurrences: four patients showed a proximal DVT (3 with a previous unprovoked ID-DVT, 1 with a previous ID-DVT secondary to a traumatic leg fracture, with persistent difficulty of deambulation); one, with a previous secondary thrombosis, showed a ID-DVT. CONCLUSIONS: In our study only 2.9% of patients with ID-DVT showed a progression of thrombosis to proximal deep veins; the majority of thrombus progression, during the treatment period, was observed in patients with unprovoked ID-DVT. Our results support the usefulness of a prolonged treatment in unprovoked ID-DVT.