Roberto Antonio Mangiafico

Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss.

CONTEXT Sclerostin, a Wnt signaling antagonist on the osteoblasts produced by osteocytes, is regulated by mechanical strain and is implicated in the pathogenesis of disuse bone loss. There are no data on sclerostin in humans. OBJECTIVE The aim of the study was to evaluate sclerostin in patients immobilized after stroke, compared with control subjects, and to analyze its relationship with markers of bone formation and resorption. DESIGN This was a cross-sectional study. SETTING AND PATIENTS We studied 40 postmenopausal women immobilized after a single episode of stroke 6 months or longer after onset, and 40 postmenopausal women from the general community. Bone status was assessed by quantitative ultrasound measurements at the calcaneus. Bone alkaline phosphatase (b-AP), carboxy-terminal telopeptide of type I collagen (CrossLaps), and sclerostin were evaluated by ELISA. We also used ELISA to measure serum levels of Dickkopf-1, another soluble inhibitor of Wnt/beta-catenin signaling, highly expressed by osteocytes. RESULTS Immobilized patients had higher sclerostin serum levels (median 0.975 ng/ml; 25th to 75th percentiles 0.662-1.490) than controls (median 0.300 ng/ml; 25th to 75th percentiles 0.165-0.400: P < 0.0001) and an increased bone turnover with a more significant rise in bone resorption (CrossLaps) than formation (b-AP) markers. Sclerostin correlated negatively with b-AP (r = -0.911; P < 0.0001) and positively with CrossLaps (r = 0.391; P = 0.012). Dickkopf-1 did not significantly differ between the groups. Patients also had quantitative ultrasound measurements index lower than controls (P < 0.001). CONCLUSIONS This study shows for the first time that long-term immobilized patients present hypersclerostinemia associated with reduced bone formation, and suggests that sclerostin could be a link between mechanical unloading and disuse osteoporosis in humans.

Increased prevalence of peripheral arterial disease in osteoporotic postmenopausal women

The aim of this study was to investigate the prevalence and correlates of peripheral arterial disease (PAD) in a population of osteoporotic postmenopausal women. The presence of PAD was assessed by ankle brachial index (ABI) in 345 ambulatory osteoporotic postmenopausal women, and in 360 community-based, age- and race-matched postmenopausal women with normal bone mineral density (BMD) (control group). PAD was detected in 63/345 (18.2%) osteoporotic women and in 14/360 (3.8%) control subjects (P < 0.0001). The mean ABI values were significantly lower in the osteoporosis group than in the control group (0.98 ± 0.09 vs. 1.04 ± 0.06, P < 0.0001). No difference in cardiovascular risk factors was observed between osteoporotic patients and controls, or between osteoporotic patients with and without PAD. Osteoporotic patients with PAD had lower femoral neck BMD T scores than those without PAD (−4.2 ± 0.7 vs. −2.3 ± 0.7, P < 0.0001). Only 4 PAD patients (5.1%) had intermittent claudication. In multivariate logistic regression analysis, factors independently associated with PAD within osteoporotic patients were lower femoral neck BMD T score (odds ratio (OR) = 0.20, 95% confidence interval (CI), 0.05–0.70, P = 0.01) and systolic blood pressure (OR = 1.02, 95% CI, 1.00–1.03, P = 0.01). This study shows for the first time an increased prevalence of PAD among osteoporotic postmenopausal women, with a lower femoral neck BMD T score being a significant independent predictor. The findings suggest that vascular status evaluation should be done in osteoporotic postmenopausal women in order to identify candidate patients for preventive and therapeutic cardiovascular interventions.

Exaggerated endothelin release in response to acute mental stress in patients with intermittent claudication.

Endothelin-1 (ET-1) is an endothelial-derived 21-amino-acid peptide with potent vasocon strictor and mitogenic properties implicated in several cardiovascular disorders. To evaluate the plasma ET-1 response to mental stress in patients with intermittent claudication, plasma endothelin concentrations were measured by radioimmunoassay in 15 claudicant outpatients (13 men and 2 women; mean age 62 ±4 years) and in 15 sex- and age-matched healthy control subjects (12 men and 3 women; mean age 60 ±8 years) before and after mental arithmetic performed for 10 minutes. Venous blood samples were drawn from an antecubital vein at baseline, at the end of the mental arithmetic, and at 10 minutes of recovery. Baseline ET-1 values were higher in patients with intermittent claudication as compared with control subjects (4.5 ±0.5 pmol/L and 2.2 ±0.3 pmol/L, respectively, p<0.0001). At the end of mental stress, ET-1 levels rose significantly in both groups from baseline (p < 0.00 1 ) reaching a higher value in patients with intermittent claudication than in control subjects (5.6 ±0.7 pmol/L and 2.4 ±0.4 pmol/L, respectively, p < 0.0001). The percent increases (Δ%) in ET-1 plasma concen trations from baseline in response to mental stress were significantly greater in claudicant patients than in control subjects (+23 ±9% and +9 ±7%, respectively, p < 0.0001). ET-1 plasma concentrations returned to baseline values similarly in both groups at minute 10 of the recovery period. These findings show that acute mental stress causes an exaggerated release of ET-1 in patients with intermittent claudication and suggest that this could be a potential pathophysiological mechanism through which mental stress may trigger adverse acute cardiac events and accelerate progression of atherosclerosis in these patients.

Hepatitis C-associated osteosclerosis (HCAO): report of a new case with involvement of the OPG/RANKL system

We report a new case of hepatitis C-associated osteosclerosis (HCAO). The clinical presentation of the patient was an acquired deep severe bone pain with increased serum bone alkaline phosphatase activity (up to 12 times the upper limit of normal), and generalized bone sclerosis, temporally related to the hepatitis C-virus (HCV) infection. We documented in this patient an increase of circulating osteoprotegerin (OPG), and a concentration of circulating receptor activator for nuclear factor-kB ligand (RANKL) below the lower limit of the reference range. The observed abnormalities of the OPG/RANKL system may contribute to the maintenance of the positive balance of bone remodeling that characterizes patients with HCAO.

Impact of a 4-week treatment with prostaglandin E1 on health-related quality of life of patients with intermittent claudication

Intermittent claudication impairs functional status and quality of life in many patients by limiting walking capacity. The aim of this study was to evaluate the effects of a 4-week treatment with prostaglandin E1 (PGE1), a drug inducing vasodilation and inhibiting platelet aggregation, on improving functional status and health-related quality of life in patients with disabling intermittent claudication. Forty-two untrained outpatients (37 men and five women, mean age 64 ±8 years) with intermittent claudication, and maximum walking distance (MWD) of at least 50 and no more than 200 m on treadmill test (5% slope, 3 km/hr) were randomized to 4 weeks of double-blind treatment either with 60 mcg PGE1 daily given IV in 250 mL saline over a period of 2 hours (21 patients) or placebo (250 mL saline, 21 patients). Treatment-free follow-up was completed 8 weeks after the final infusion. Pain free walking distance (PFWD), MWD, and questionnaire evaluation were determined at baseline, after the 4-week treatment period, and at the end of the 8 weeks of the treatment-free follow-up period. After 4 weeks of treatment with PGE1 PFWD and MWD increased from 72 ±16 m to 135 ±33 m (+87%, p<0.001) and from 140 ±30 m to 266 ±62 m (+90%, p<0.001), respectively. Analysis of the Walking Impairment Questionnaire responses in the PGE1 group at 4 weeks demonstrated significant improvements in the walking impairment score (+ 19 percentage points, p<0.001), in the distance score (+25 percentage points, p<0.001), in the speed score (+24 percentage points, p<0.001), in the stair climbing score (+20 percentage points, p< 0.001). The RAND survey responses showed improvements in physical function and bodily pain scores (+ 14 percentage points, p<0.001, and + 15 percentage points, p<0.01, respectively). After the treatment-free follow-up period of 8 weeks, increases in PFWD and MWD were maintained (113 ±26 m, +57%, p<0.001, and 229 ±55 m, + 63%, p<0.001, respectively). Similarly, at the end of the treatment-free follow-up, the walking impairment score (+16 percentage points, p<0.001), the distance score (+23 percentage points, p<0.001), the speed score (+22 percentage points, p<0.001), the stair climbing score (+18 percentage points, p<0.001) as well as the RAND physical function and bodily pain scores (+ 10 percentage points, p<0.001, and + 13 percentage points, p<0.01, respectively) were still increased compared with baseline. No change from baseline was found in all the target parameters in the placebo group after 4 weeks of treatment and at the end of the treatment-free follow-up period. These data show that a 4-week treatment with PGE1 improves functional status and quality of life as well as treadmill performance in patients with disabling intermittent claudication as compared with placebo-treated patients. The improvements are also maintained for a period of 8 weeks beyond the end of the treatment. Additional studies are needed to determine the duration of functional benefits after the end of treatment.

Plasma endothelin-1 concentrations during cold exposure in essential acrocyanosis

To assess endothelin-1 (ET-1) response to cold stimulation in essential acrocyanosis (EA), the authors measured ET-1 plasma concentrations in 6 patients with EA (6 women, age range seventeen to thirty-seven years) and in 6 controls (5 women, 1 man, age range twenty-one to thirty-seven years) before and after cold challenge by unilateral hand immersion in water bath at 13°C for five minutes. The contralateral upper limb was considered as control. Blood samples were simultaneously drawn from an antecubital vein in the cooled side and in the contralateral upper limb at baseline, at the end of cooling, and at ten and ninety minutes after cooling was begun. Plasma ET-1 was deter mined by a radioimmunoassay system. Results are mean ±SD. Baseline ET-1 was higher in patients with EA (5.1 ±0.3 pmol/L) than in controls (1.9 ± 0.1 pmol/L, P < 0.001). After hand cooling, ET-1 in the cold-exposed upper limb rose in patients with EA to a peak value of 7.2 ±0.7 pmol/L, which was greater than that observed in healthy subjects (2.7 ±0.4 pmol/L, P < 0.001). The absolute increase in ET-1 plasma concentrations from baseline to peak value was significantly higher in patients with EA than in controls (2.1 ±0.3 vs 0.8 ± 0.2 pmol/L, respectively, P < 0.001). In patients with EA, but not in controls, the rise in ET-1 plasma concentrations was still detected ninety minutes after cooling. The same time course of the plasma ET-1 concentrations was observed in the noncooled upper limb, but the increases in ET-1 at different times after cold stimulus were smaller than in the cold-challenged upper limb in both groups (P < 0.001). In conclusion, the results demonstrate that in patients with EA, baseline plasma levels of ET-1 are enhanced and are further increased by cooling until ninety minutes after cold challenge. This rise in plasma ET-1 could contribute to potentiating and prolonging cold-induced vasoconstric tion/vasospasm and/or could be a marker for endothelial damage in EA.

The association between carotid or femoral atherosclerosis and low bone mass in postmenopausal women referred for osteoporosis screening. Does osteoprotegerin play a role

Atherosclerosis and osteoporosis appear to be epidemiologically correlated. Most (but not all) animal and clinical studies suggest that osteoprotegerin (OPG) may represent a possible molecular link between bone loss and vascular calcification. The aim of this study was to investigate the association of OPG with bone mineral density (BMD) and vascular plaques, in order to contribute to a better understanding of the link between atherosclerosis and osteoporosis. The study population consisted of 100 consecutive postmenopausal women referred for routine osteoporosis screening. BMD was evaluated by dual-energy X-ray absorptiometry. Presence of carotid or femoral plaques was examined by ultrasonography. OPG was measured by enzyme immunoassay. Seventy-two subjects had low bone mass and were categorized as osteopenic (32) or osteoporotic (40). Fifty-two subjects had one or more atherosclerotic plaques at carotid or femoral level. Both lumbar spine and femoral BMD were associated with the number of plaques (r=-0.5370; p<0.0001, and r=-0.4423; p=0.0012, respectively), however only spine BMD remained significantly associated with the number of plaques after adjustment. OPG serum values showed a significant association with age (r(2)=0.057; p=0.042). The association between OPG and the number of plaques was significant only in patients with concomitant involvement of carotid and femoral districts (r(2)=0.758; p<0.0001).

Medical treatment of critical limb ischemia: current state and future directions.

Atherosclerotic critical limb ischemia (CLI) is manifested by ischemic rest pain, non-healing ulcers or gangrene. The incidence of CLI is estimated to be approximately 500-1000 new cases per year per million people and is expected to grow in developed countries as the population ages with an increasing prevalence of diabetes. Patients diagnosed with CLI are at very high risk of major amputation and cardiovascular morbidity and mortality and experience poor physical function and quality of life. The goals of treatment for CLI are relieving ischemic pain, healing ulcers, preventing limb loss, improving patient function and quality of life, and prolonging survival. Prompt surgical or endovascular revascularization is currently recommended for limb salvage in CLI. All patients with CLI should receive cardiovascular risk reduction therapies, focused on optimizing antiplatelet therapy and risk factor management, to reduce cardiovascular event rates. Adjunctive pharmacotherapy with antithrombotic drugs, statins, and beta-blockers is critical to decrease perioperative cardiovascular complications in patients undergoing surgical vascular reconstruction and enhance postrevascularization arterial and graft patency. In non-reconstructable patients with stable pain and tissue loss, evidence suggests that prostanoids, dedicated wound care programs, and several mechanical devices, such as spinal cord stimulation, intermittent pneumatic compression, and hyperbaric oxygen therapy, can alleviate ischemic symptoms and improve limb salvage. Current medical armamentarium used in treating ischemic wounds also includes ultrasound and negative pressure wound therapy. Therapeutic neovascularization, including gene- and cell-based approaches, is a novel promising tool in the management of CLI under ongoing investigation.

Current management of intermittent claudication: the role of pharmacological and nonpharmacological symptom-directed therapies.

Lower extremity peripheral arterial disease (PAD) is a manifestation of atherosclerosis, with a prevalence ranging from 4% to 12% in the adult population and increasing up to 20% in older individuals. Intermittent claudication (IC) may markedly impair walking ability, overall functional status and quality of life. PAD is a marker of systemic atherosclerosis and is associated with increased cardiovascular morbidity and mortality. However, leg disease usually runs a rather benign course in claudicant patients, with only about 1% to 3% of them ever requiring a major amputation over a 5-year period. The goals of treatment for claudication are to relieve exertional symptoms, and improve walking capacity and quality of life. Therapeutic strategies aimed at reducing systemic cardiovascular risk burden and prolonging survival, including intensive risk factor modification and antiplatelet therapy, should be implemented in all patients with PAD. Supervised exercise training has proven the most effective conservative treatment for symptomatic relief of IC. Current evidence for drug therapy of IC supports the use of cilostazol as a first-line drug. Other drugs with more limited evidence of benefit for claudication include pentoxifylline and naftidrofuryl. Endovascular or surgical revascularization is indicated for selected patients with vocation- or lifestyle-limiting claudication who are unresponsive to exercise and pharmacotherapy. New drug candidates for managing claudication symptoms include propionyl-L-carnitine and statins. Preliminary studies suggest that therapeutic angiogenesis holds promise for future treatment of IC.

Plasma Endothelin-1 Release in Normal and Varicose Saphenous Veins

The aim of the study was to investigate the release of endothelin-1 (ET-1) in normal and varicose saphenous veins at baseline and after venous stasis test. Ten patients (eight women and two men, mean age 43 ±4) with primarily varicose great saphenous veins and ten controls (eight women and two men, mean age 42 ±6) were recruited. After 30 minutes of resting in supine position, venous occlusion in a leg was performed with a sphygmomanometer provided to keep the pressure in the cuff intermediate between systolic and diastolic blood pressure for 10 minutes. Blood samples were taken from the great saphenous vein just above the medial malleolus at baseline and 10 minutes after venous stasis was begun. Plasma ET-1 was determined by a radioimmunoassay system. Results are expressed as mean ±SD. Plasma ET-1 concentration was higher in varicose than in normal saphenous veins (4 ±0.1 pmol/L vs 2.6 ±0.1 pmol/L, P<0.001), and it significantly increased (P<0.001) in both groups after venous stasis when compared with baseline (6.8 ±0.9 pmol/L and 3.6 ±0.1 pmol/L in varicose and normal saphenous veins, respectively). Absolute increase in plasma ET-1 was significantly greater in varicose than in normal saphenous veins (2.8 ±0.9 pmol/L vs 1.0 ±0.2 pmol/L, P<0.01). In conclusion, increased local ET-1 release in varicose saphenous veins could be a marker for venous endothelial activation/damage and/or contribute to promote the morphologic alterations of the varicose vein wall by stimulating smooth muscle cell prolif eration. On the other hand, increased ET-1 release could contribute to counterbalancing the varicose venous relaxation and to increasing preload in varicose patients via ET-1- induced venoconstriction.