Guido Salvetti

Age-Related Reduction of NO Availability and Oxidative Stress in Humans

Abstract—Age-related endothelial dysfunction could be caused by an alteration in the l-arginine-NO system and the production of oxidative stress in both normotensive and hypertensive individuals. In 47 normotensive subjects and 49 patients with essential hypertension, we evaluated forearm blood flow (by strain-gauge plethysmography) modifications induced by intrabrachial sodium nitroprusside (1, 2, and 4 &mgr;g/100 mL per minute) and acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 &mgr;g/100 mL per minute), an endothelium-independent vasodilator and an endothelium-dependent vasodilator, respectively. Acetylcholine was repeated in the presence of the NO synthase inhibitor NG-monomethyl-l-arginine (L-NMMA, 100 &mgr;g/100 mL per minute), the antioxidant vitamin C (8 mg/100 mL per minute), or both. Vasodilation to acetylcholine, but not to sodium nitroprusside, was lower (P <0.01) in hypertensive patients compared with control subjects. Moreover, in both groups, endothelium-dependent vasodilation declined with aging. In normotensive subjects, the inhibiting effect of L-NMMA on response to acetylcholine decreased in parallel with advancing age, whereas vitamin C increased vasodilation to acetylcholine in only the oldest group (age >60 years). In young hypertensive patients (age <30 years), vasodilation to acetylcholine was sensitive to L-NMMA, whereas in hypertensive patients age >30 years, vitamin C enhanced endothelium-dependent vasodilation and restored the inhibiting effect of L-NMMA on response to acetylcholine. In normotensive individuals, an earlier primary dysfunction of the NO system and a later production of oxidative stress cause age-related reduction in endothelium-dependent vasodilation. These alterations are similar but anticipated in hypertensive patients compared with normotensive subjects.

Physical Activity Prevents Age-Related Impairment in Nitric Oxide Availability in Elderly Athletes

BACKGROUND Aging is associated with increased cardiovascular risk and endothelial dysfunction. Since exercise can improve endothelium-dependent vasodilation, in the present study we tested whether long-term physical activity could prevent aging-related endothelial dysfunction. METHODS AND RESULTS In 12 young and elderly (age 26.9+/-2.3 and 62.9+/-5.8 years, respectively) healthy sedentary subjects and 11 young and 14 elderly matched athletes (age 27.5+/-1.9 and 66.4+/-6.1 years, respectively), we studied (with strain-gauge plethysmography) forearm blood flow modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 microg/100 mL per minute), an endothelium-dependent vasodilator, at baseline, during infusion of N(G)-monomethyl-L-arginine (L-NMMA) (100 microg/100 mL forearm tissue per minute), a nitric oxide-synthase inhibitor, vitamin C (8 mg/100 mL forearm tissue per minute), an antioxidant, and finally under simultaneous infusion of L-NMMA and vitamin C. The response to sodium nitroprusside (1, 2, and 4 microg/100 mL forearm tissue per minute) was also evaluated. In young athletes and sedentary subgroups, vasodilation to acetylcholine was inhibited by L-NMMA and was not changed by vitamin C. In elderly subjects, vasodilation to acetylcholine was blunted as compared with young subjects in both control subjects and athletes, whereas the response to sodium nitroprusside was similar. Moreover, in elderly athletes, vitamin C did not change the vasodilation to acetylcholine. In contrast, in elderly sedentary subjects, the response to acetylcholine was resistant to L-NMMA. In this subgroup, vitamin C increased the vasodilation to acetylcholine and restored the inhibiting effect of L-NMMA. CONCLUSIONS These results suggest that regular physical activity can at least in part prevent the age-induced endothelial dysfunction, probably the restoration of nitric oxide availability consequent to prevention of production of oxidative stress.

Mechanisms responsible for endothelial dysfunction induced by fasting hyperhomocystinemia in normotensive subjects and patients with essential hypertension

OBJECTIVES We sought to evaluate whether fasting hyperhomocystinemia reduces endothelial function by oxidative stress in normotensive subjects and hypertensive patients. BACKGROUND Subjects with hyperhomocystinemia have endothelial dysfunction. METHODS In 23 normotensive subjects and 28 hypertensive patients, classified into normohomocystinemic and hyperhomocystinemic groups according to homocysteine plasma levels (< 8.7 and >14.6 micromol/l, respectively), we studied forearm blood flow changes (strain-gauge plethysmography) induced by intrabrachial administration of acetylcholine (0.15 to 15 microg/100 ml tissue per min) or sodium nitroprusside (1 to 4 microg/100 ml per min), an endothelium-dependent and -independent vasodilator, respectively. Acetylcholine was repeated with N(G)-monomethyl-L-arginine (L-NMMA; 100 microg/100 ml per min), vitamin C (8 mg/100 ml per min) and L-NMMA plus vitamin C. RESULTS Normotensive hyperhomocystinemic patients showed a blunted response to acetylcholine and a lower inhibiting effect of L-NMMA on acetylcholine, as compared with normohomocystinemic patients. Although vitamin C was ineffective in normohomocystinemic subjects, it increased the response to acetylcholine and restored the inhibiting effect of L-NMMA on acetylcholine in hyperhomocystinemic patients. Hypertensive hyperhomocystinemic patients showed a reduced response to acetylcholine, as compared with normohomocystinemic subjects. In both subgroups, L-NMMA failed to blunt the response to acetylcholine. The potentiating effect of vitamin C on acetylcholine was greater in hyperhomocystinemic patients than in normohomocystinemic subjects, although it restored the inhibitory effect of L-NMMA on acetylcholine-induced vasodilation to the same extent in both groups. Hyperhomocystinemia did not change the response to sodium nitroprusside. CONCLUSIONS In normotensive subjects and hypertensive patients, hyperhomocystinemia impairs endothelium-dependent vasodilation. It could be related to oxidant activity.

Vascular Generation of Tumor Necrosis Factor-α Reduces Nitric Oxide Availability in Small Arteries From Visceral Fat of Obese Patients

OBJECTIVES The aim of this study was to assess whether small arteries from visceral fat of obese patients show a reduced nitric oxide (NO)-dependent relaxation, as compared with lean control subjects, focusing on the role of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α. BACKGROUND Visceral obesity is characterized by endothelial dysfunction. METHODS Small arteries from 14 obese (body mass index 48.4 ± 11 kg/m(2)) and 14 control subjects (body mass index 24.9 ± 2 kg/m(2)), dissected after a visceral fat biopsy (laparoscopy), were evaluated on a pressurized micromyograph. Endothelium-dependent relaxation was assessed by acetylcholine. The NO availability, superoxide production, and inflammation were assessed by testing acetylcholine under the nitric oxide synthase (NOS) inhibitor N(ω)-nitro-L-arginine methylester, tempol (superoxide scavenger), and infliximab (monoclonal anti-TNF-α antibody), respectively. The roles of nicotinamide adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase (iNOS) were assessed by their selective inhibitors apocynin and S-methylisothiourea (SMT), respectively. Vascular superoxide generation (dihydroethidium staining) protein expression of TNF-α and NOS isoforms (Western Blot) and TNF-α localization (immunohistochemistry) were assessed. RESULTS Vessels from obese patients displayed a blunted relaxation to acetylcholine and a reduced inhibitory effect of N(ω)-nitro-L-arginine methylester. These alterations were normalized by tempol or infliximab while being partly ameliorated by apocynin and SMT. Vascular superoxide generation was increased (p < 0.01) in obese patients. This condition was abrogated by both tempol and infliximab and partly (p < 0.05 vs. control subjects) reduced by apocynin or SMT. Enhanced TNF-α and iNOS expression together with increased TNF-α localization in the vascular media were detected. CONCLUSIONS Small arteries from visceral fat of obese patients are characterized by an increased TNF-α production, which reduces NO availability by promoting superoxide generation via nicotinamide adenine dinucleotide phosphate oxidase and iNOS activation.

Melanocortin-4 receptor mutations in obesity

The current alarming spread of obesity in many parts of the world is caused by a sudden environmental shift characterized by replacement of a frugal diet with low cost, energy dense food, and little requests for physical activity during work and leisure time. Yet, not all people exposed to an obesogenic environment become obese, and individual differences in the propensity to gain weight as well as the occurrence of different obese phenotypes within the same environment indicate that the genetic heritage in this regard is significant and heterogeneous. The central melanocortin circuit has received much attention during the past decade, since mutations of genes expressing some key molecules in neurons of this system were discovered, which may cause monogenic forms of obesity in animals and humans. Within the arcuate nucleus of the hypothalamus the prohormone proopiomelanocortin is posttranslationally cleaved to produce the alpha-melanocyte stimulating hormone, a peptide with anorexigenic effects upon activation of the melanocortin-4 receptor (MC4R) expressed on the surface of target neurons. Studies regarding the frequency of MC4R mutations associated with human obesity have provided variable results (up to 6% of obese subjects). Various findings suggest an oligogenic and codominant mode of inheritance for MC4R deficiency, with modulation of expressivity and penetrance of the phenotype. The yield of MC4R testing in clinical diagnosis and treatment of obesity is at present undefined since the relatively low prevalence of MC4R pathogenic variants in the general population, along with the high number of sequence variants, has so far compromised the devising of systematic controlled intervention studies. Hopefully, in the future, MC4R testing will have practical implications for the development of new mechanism-based therapy of obesity as well as for the design of specific and more effective protocols, based on lifestyle intervention and current pharmacological or surgical approaches, for management of obesity in MC4R-mutated individuals.

Calcium Antagonist Treatment by Lercanidipine Prevents Hyperpolarization in Essential Hypertension

Abstract—Essential hypertension is associated with impaired endothelium-dependent vasodilation caused by oxidative stress-induced nitric oxide (NO) breakdown and compensatory production of a hyperpolarizing factor. To test whether calcium antagonist treatment can restore NO availability and prevent hyperpolarization through antioxidant properties, in 15 healthy subjects and 15 patients with essential hypertension, we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial bradykinin (5, 15, 50 ng/100 mL per minute), an endothelium-dependent vasodilator, in basal conditions, during infusion of NG-monomethyl-l-arginine (L-NMMA, 100 &mgr;g/100 mL per minute), an NO-synthase inhibitor, and ouabain (0.72 &mgr;g/100 mL per minute), an Na+-K+ ATPase inhibitor to prevent hyperpolarization. These infusions were repeated in the presence of the antioxidant vitamin C (8 mg/100 mL/min). The response to sodium nitroprusside was also evaluated. In controls, vasodilation to bradykinin was inhibited by L-NMMA and remained unchanged by ouabain or vitamin C. In hypertensive patients, vasodilation to bradykinin was blunted and resistant to L-NMMA but sensitive to ouabain. Vitamin C increased the response to bradykinin and restored the inhibiting effect of L-NMMA while preventing the effect of ouabain. In hypertensive patients, infusions were repeated after 3-month treatment with lercanidipine (10 to 20 mg daily). Lercanidipine decreased plasma lipoperoxides, isoprostanes, and malondialdehyde and increased plasma antioxidant capacity. Moreover, lercanidipine increased the vasodilation to bradykinin and restored the inhibiting effect of L-NMMA on bradykinin-induced vasodilation while preventing the effect of ouabain. Finally, vitamin C no longer exerted its facilitating activity. These results indicate that in essential hypertension, lercanidipine increases endothelium-dependent vasodilation by restoring NO availability and preventing hyperpolarization, an effect probably determined by antioxidant activity.

Endothelial function in hypertension: role of gender

Classification of the severity of hypertension and recommendations on the blood pressure values to be achieved during antihypertensive drug treatment have for decades been based on diastolic values. It is now clear, however, that systolic blood pressure is by no means less important. This paper will focus on the following sets of evidence: (1) that epidemiologically a selective elevation of systolic blood pressure has a major prevalence in the elderly population; (2) that isolated systolic hypertension carries a marked increase in the risk of cardiovascular disease and that even in systo-diastolic hypertension this risk may be more closely related to systolic than to diastolic blood pressure; (3) that treatment of systolic hypertension greatly reduces cardiovascular complications and that in all conditions this reduction is related to the treatment-induced reduction in systolic blood pressure to a degree similar to or superior to the relationship with the reduction in diastolic blood pressure; and (4) that in the hypertensive fraction of the population, control of systolic blood pressure is achieved much less often than control of diastolic blood pressure. That this last point is also the case in major intervention trials suggests that normalization of systolic blood pressure may be intrinsically more difficult than normalization of diastolic blood pressure, possibly because of the difficulty of reversing the pathophysiological abnormalities responsible for the elevation of systolic blood pressure. This emphasizes the importance of research into new drugs or treatment types with greater efficacy in systolic hypertension.Cyclooxygenase (COX) constitutes the rate-limiting enzyme in the biosynthetic cascade of prostaglandin (PG). Evidence has accrued suggesting pathophysiological states with altered COX-2 activity and expression. Recent experimental evidence suggests that COX-2 has a pathogenetic role in some of these derangements. In other situations, the effect of altered COX-2 regulation is unclear or possibly beneficial. These processes suggest new areas for potential use of COX-2-specific inhibitors. Conversely, in some conditions COX-2-specific inhibitors should be avoided. The conventional view is that COX-2 is an inducible enzyme. However, COX-2 is also active in the constitutive production of prostanoids in the kidney. Consequently, the pathophysiological states discussed herein include not only COX-2 induction during inflammation but also derangements in COX-2 expression and function caused by non-inflammatory stimuli.Arterial hypertension and diabetes mellitus are two important and frequent risk factors for atherosclerosis and their association in the same patients is particularly elevated, suggesting something more than the simple causality due to their frequency. In women with diabetes mellitus, the risk of cardiovascular complications is similar to that in men with diabetes mellitus, a pattern completely different from that in the general population where the cardiovascular risk in women is significantly lower than in men. During the gestational period, the glucose metabolism may be reduced and there may be an elevation of blood pressure with or without proteinuria and both conditions have a negative prognostic impact for the mother and for the fetus. On the contrary, reduced glucose tolerance during pregnancy does not seem to represent an important risk factor. The advent of ambulatory blood pressure monitoring has allowed one to evaluate in more detail the pattern of blood pressure in normal pregnancy or pregnancy complicated by diabetes mellitus or hypertension.Recent studies have investigated the renal and cardiovascular safety of celecoxib and rofecoxib. Both agents have been studied in long-term safety trials: the Celecoxib Long-Term Safety Study (CLASS) and Vioxx Gastrointestinal Outcomes Research Study (VIGOR). Renal safety was investigated in CLASS and the results indicated that celecoxib (even at the supratherapeutic 800 mg daily doses used in CLASS) is associated with lower rates of renal side effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). The renal safety of celecoxib was also assessed in healthy elderly subjects. In these subjects, celecoxib administration was associated with minimal effects on glomerular filtration rate compared with naproxen, while urinary sodium and prostaglandin E2 excretion were similar. Celecoxib and rofecoxib were compared with each other in two studies of elderly hypertensive patients with osteoarthritis (OA). These patients were treated with usual therapeutic doses of celecoxib (200 mg daily) or rofecoxib (25 mg daily). In the first study, celecoxib treatment had a significantly lower incidence of peripheral oedema than rofecoxib (4.9% versus 9.5%, P = 0.014). The second study confirmed the results of the initial study: the incidence of oedema was again lower with celecoxib than with rofecoxib (4.7% versus 7.7%, P < 0.05). Rofecoxib use was also associated with significantly greater mean and clinically relevant increases in systolic blood pressure than celecoxib. The CLASS study, which evaluated cardiovascular safety, showed that celecoxib treatment was not associated with an increase in myocardial infarction (MI) compared with non-selective NSAIDs (incidence in all patients was 0.3% for celecoxib and 0.3% for conventional NSAIDs). In a 12-week study of celecoxib (the Successive Celecoxib Efficacy and Safety Studies, SUCCESS-1) in more than 13000 patients with OA, combined doses of celecoxib (200 mg and 400 mg daily) and conventional NSAIDs (naproxen 1000 mg daily and diclofenac 100 mg daily) were again associated with similar rates of cardiovascular adverse events, including MI. However, in the VIGOR trial, treatment with rofecoxib was associated with a significantly higher rate of MI compared with naproxen (0.4% compared with 0.1% in the naproxen group, P < 0.05). In summary, celecoxib may have safety and tolerability advantages compared with non-selective NSAIDs studied and may have some cardiorenal benefits compared with rofecoxib.Stroke represents a severe and growing health problem in the general population. The increasing burden of disease associated with stroke appears to be largely related to progressive ageing of the population, and in fact is increasing more rapidly in women than in men. In addition, emerging pathophysiological, clinical and therapeutic issues confer specific characteristics to stroke in women. This article briefly covers some of the most important of these aspects.PURPOSE The aim of this review is to summarize the evidence from randomized controlled trials and meta-analyses of hypertension treatment trials that included women in their study population and subsequent analyses. RESULTS Most early hypertension treatment trials did not include women in their study population, or did so in insufficient numbers to assess gender-specific outcomes. Women, particularly the elderly, were better represented in subsequent studies, but gender-specific results were not often reported and most trials were not designed or powered to detect gender differences in treatment responses and outcomes. In some studies where gender-specific results have been reported, gender differences have been observed, but the direction of the effect has generally been similar in men and women. Large meta-analyses of treatment trials have found similar relative risk reductions as a result of hypertension treatment, but lower absolute risk reductions in women compared to men. Absolute risk reductions are strongly related to baseline risk and have been demonstrated in virtually all subgroups of women except those with extremely low aggregate cardiovascular risk. While there are still limited data regarding treatment benefits for young women, no subset of women has been shown to experience net harm as a result of hypertension therapy. CONCLUSION The design and implementation of future hypertension treatment trials should include the provision to assess gender-specific differences in treatment and outcomes.Endothelium plays an important role in the modulation of vascular tone and structure mainly through the production of nitric oxide (NO), which causes local vasodilation and counteracts processes leading to atherothrombosis. A dysfunctioning endothelium, characterized by reduced NO availability owing to impairment of the L-arginine-NO pathway and, above all, to production of oxygen free radicals, can impair local vasomotion and promote the development of atherosclerosis and of atherothrombotic vascular events. Aging is associated with endothelial dysfunction both in normotensive subjects and in hypertensive patients, and hypertension seems to induce earlier onset of those mechanisms (i.e. impairment of the L-arginine-NO pathway and oxidative stress) that cause age-related endothelial dysfunction. Premenopausal normotensive women are protected against the deleterious effect of aging on endothelial function, and age-related impairment of endothelial function is attenuated in premenopausal hypertensive women. This protective effect on endothelial function seems to be mediated by endogenous estrogen, which preserves NO availability by activating the L-arginine-NO pathway in normotensive women and, again, by activating this pathway but above all by inhibiting oxidative stress in hypertensive women. Thus, the protective effect of endogenous estrogen on endothelial function could be a plausible mechanism contributing to the lower cardiovascular risk of premenopausal women. Finally, whether endogenous androgen can impair endothelial function is still an unsolved issue since data concerning the effect of testosterone on endothelial function are scanty and contradictory.Although during the past two decades there has been considerable progress in the understanding of the pathophysiology of human essential hypertension, the basic mechanisms responsible for the development and progression of the disease still remain largely undefined. This also applies to the pathophysiology of hypertension in women, although a number of haemodynamic, vascular, metabolic and neurohumoral factors have been identified throughout the years as being characterized by a gender-specific relation. This paper will examine the main differences in the haemodynamic, vascular, metabolic and neurohumoral profile characterizing normotensive as well as hypertensive females as compared with age-matched males. Although in some instances clearcut differences between genders can be found, overall the pathophysiological picture of the hypertensive state does not seem to have significant differences in men and women, at least up to the years when the menopausal-related hormonal changes take place.To study whether prevention of renal injury using the anti-inflammatory drugs pentosan polysulphate (PPS) and mycophenolate mofetil (MMF) is associated with improvement of glomerular haemodynamics, PPS and MMF were compared with losartan. The awake systolic blood pressure (SBP), proteinuria (Uprot) and micropuncture studies were performed 30 days after five-sixths nephrectomy in untreated rats and in rats treated with PPS (100 mg/kg per day), MMF (30 mg/kg per day) or losartan (30 mg/kg per day). In the rats receiving no treatment, there was a rise in SBP (to 180-200 mmHg) and in Uprot, which were prevented by losartan. In the PPS and MMF groups, the SBP was elevated but the Uprot did not increase. In the untreated rats the total glomerular filtration rate (GFR) decreased (-80%) and the single-nephron GFR (37-42%), plasma flow (67-127%) and glomerular pressure (10-15 mmHg) increased. These changes were prevented by PPS and MMF to the same extent as by losartan: the rise in single-nephron GFR and plasma flow were reduced by 50% and the glomerular pressure was normal. In rats receiving losartan, this was due to the fall in arterial pressure, whereas in PPS- and MMF-treated rats it was due to a rise in afferent resistance, indicating autoregulatory capacity. Total GFR was similar, despite the lower single-nephron GFR in treated groups, suggesting a larger proportion of functioning nephrons. Losartan, PPS and MMF significantly reduced glomerular sclerosis and tubular dilation and atrophy in association with a reduction in the lymphocyte and macrophage infiltrate. These results suggest an interaction between the haemodynamic and inflammatory changes that perpetuate each other during progression of renal injury. Renal protection provided by anti-inflammatory drugs is partially mediated by the prevention of glomerular haemodynamic alterations.Early intervention studies have challenged the notion that lowering blood pressure is beneficial in women with mild hypertension. In contrast, results of more recent trials have clearly shown that treatment of hypertension is of benefit in women, particularly in elderly women. Aggressive treatment of hypertension is advisable in this subset of the population that is exposed to a greater risk of hypertension-related cardiovascular diseases because of the greater prevalence of hypertension and of its inadequate treatment. Hypertensive women are preferentially treated with diuretics but the rationale for this therapeutic selection is unclear. Calcium antagonists, beta-blockers and angiotensin-converting enzyme inhibitors exert an antihypertensive action similar to that of diuretics, but their use is limited by the adverse effects that are more frequent in women than in men. Angiotensin II receptor antagonists, being effective in lowering blood pressure and particularly well tolerated, may represent, in the future, the first-line drugs for treating hypertension in women.

Prevalence of left ventricular hypertrophy and determinants of left ventricular mass in obese women.

BackgroundObesity is frequently associated with left ventricular hypertrophy (LVH), a condition leading to an increased cardiovascular risk.AimThe objective of this study was to evaluate the prevalence of LVH in a cohort of obese women, with a main focus on the anthropometric and clinical parameters that are associated with an increased left ventricular mass (LVM).MethodsThe study was performed in 166 obese female patients. LVM was measured by echocardiography. The influence of various parameters on LVM was assessed by multivariate analysis.ResultsThe prevalence of LVH was drastically different depending on the type of indexed LVM, being 19.9% when the LVM was indexed for body surface area and 72.3% when indexed for height. Age, duration of obesity, weight, waist-to-hip ratio, pulse pressure and hypertension retained an independent direct correlation with the LVM, explaining 39.6% of the overall LVM variability. Among the parameters of the metabolic syndrome, the increase in blood pressure was the main determinant of increased LVM.ConclusionsBy using allometric indexation of LVM for height, the results of our study indicate a high prevalence of LVH in a cohort of obese women. Hypertension, pulse pressure, age, duration of obesity, bodyweight and fat distribution, expressed as waist-to-hip ratio, predict 40% of LVM variation.

Hepatic left lobe volume is a sensitive index of metabolic improvement in obese women after gastric banding

BACKGROUND:Nonalcoholic fatty liver disease is a common finding in obese subjects. Increasing evidence has been provided suggesting that it represents the hepatic component of the metabolic syndrome.OBJECTIVE:Aim of this longitudinal study was to evaluate the relationships between several anthropometric measures, including the hepatic left lobe volume (HLLV), and various indicators of the metabolic syndrome in a cohort of severely obese women before and after laparoscopic adjustable gastric banding (LAGB).STUDY DESIGN AND RESULTS:Seventy-five obese women (mean age 45±10 years and body mass index (BMI) 42.5±4.8 kg m−2) underwent LAGB and completed an average (±s.d.) post-surgical follow-up of 24±6 months. Determination of HLLV, subcutaneous and intra-abdominal fat (IAF) was based on ultrasound. The principal component statistical analysis applied to pre-operative measurements, highlighted HLLV as a parameter that clustered with serum insulin, IAF, serum glucose and uric acid, along with triglycerides (TGs), alkaline phosphatase and high-density lipoprotein cholesterol. After LAGB, the average reduction of BMI was 23%, 12% for subcutaneous fat (SCF), 42% for HLLV and 40% for visceral fat. Among body weight, BMI, SCF, IAF and HLLV, reduction of the latter was an independent predictor of reduction of serum transaminases and γ-Glutamyltransferase, glucose, insulin and TGs.CONCLUSIONS:In severely obese women: (i) HLLV is a sensitive indicator of ectopic fat deposition, clustering with parameters defining the metabolic syndrome; (ii) weight loss achieved by LAGB is associated with a reduction of liver volume as estimated by HLLV; (iii) among various anthropometric parameters measured, reduction of HLLV that follows LAGB represents the best single predictor of improvement of various cardiometabolic risk factors.

Description of an AGPAT2 pathologic allelic variant in a 54-year-old Caucasian woman with Berardinelli-Seip syndrome

A 54-year-old Italian female patient was admitted to our Department with the diagnosis of type 2 diabetes poorly controlled with insulin therapy. The patient was born by consanguineous parents (first degree cousins); she had acromegaloid features, diffuse lipoatrophy and muscular pseudo-hypertrophy since childhood. To confirm the clinical hypothesis of congenital generalized lipodystrophy (CGL) or Berardinelli-Seip syndrome, the sequences of AGPAT2 (encoding for 1-acyl-sn-glycerol-3-phosphate acyltransferase beta) and BSCL2 (encoding for seipin) candidate genes were analyzed. DNA analysis showed the presence of a homozygous mutation in exon 3 of the AGPAT2 gene (P112L). This is the first description of a Caucasian subject with CGL who carries the pathologic allelic variant P112L of the AGPAT2 gene.