Pietro Ameri

High prevalence of vitamin D deficiency and its association with left ventricular dilation: An echocardiography study in elderly patients with chronic heart failure

BACKGROUND AND AIMS Vitamin D deficiency has been associated with chronic heart failure (CHF). We evaluated vitamin D levels in relationship with New York Heart Association (NYHA) classes, N-terminal pro-brain natriuretic peptide (NT-proBNP) values and left ventricular (LV) measures in ≥60 year old patients with stable CHF. Differently from previous investigations, LV function was assessed by transthoracic echocardiography, to provide easily reproducible results. METHODS AND RESULTS The study was performed at geographic latitude 44° N, from March to May and from September to November 2008. Acute HF and diseases or drugs altering vitamin D status were exclusion criteria. NYHA scores and 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D and NT-proBNP concentrations were assessed in 90 (45 F, 45 M) Caucasian patients with CHF secondary to hypertension and/or coronary artery disease. Vitamin D levels were also measured in 31 subjects without heart disease (controls). LV echocardiography was performed in 52 (26 F, 26 M) representative patients. Vitamin D concentrations were significantly lower in CHF cases than in controls. Among subject with CHF, 97.8% presented vitamin D deficiency (25(OH)D<75 nmol/L), being severe (<25 nmol/L) in 66.7%. LV end-diastolic and end-systolic diameters were significantly longer, LV end-diastolic and end-systolic volumes bigger and fractional shortening lower in CHF patients with 25(OH)D<25 nmol/L than with 25(OH)D≥25 nmol/L (p<0.05). Log-values of 25(OH)D were negatively correlated with LV end-systolic diameter and volume (r=-0.28; p<0.05). On subgroup analysis, these results persisted only in male patients. CONCLUSIONS In elderly CHF patients, vitamin D deficiency was highly prevalent and often severe. This first addressed echocardiography study showed a sex-specific association between vitamin D deficiency and LV dilation. Since further echocardiography data are easily obtainable, larger investigations are demanded.

Alterations in the autonomic control of heart rate variability in patients with anorexia or bulimia nervosa: Correlations between sympathovagal activity, clinical features, and leptin levels

Changes in body composition, hormone secretions, and heart function with increased risk of sudden death occur in eating disorders. In this observational clinical study, we evaluated sympathovagal modulation of heart rate variability (HRV) and cardiovascular changes in response to lying-to-standing in patients with anorexia (AN) or bulimia nervosa (BN) to analyze: a) differences in autonomic activity between AN, BN, and healthy subjects; b) relationships between autonomic and cardiovascular parameters, clinical data and leptin levels in patients with eating disorders. HRV, assessed by power spectral analysis of R-R intervals, blood pressure (BP) and heart rate (HR) were studied by tilt-table test in 34 patients with AN, 16 with BN and 30 healthy controls. Autonomic and cardiovascular findings were correlated with clinical data, and serum leptin levels. Leptin levels were lowered in AN vs BN and healthy subjects (p<0.0001), but both AN and BN patients showed unbalanced sympathovagal control of HRV due to relative sympathetic failure, prevalent vagal activity, impaired sympathetic activation after tilting, independently from their actual body weight and leptin levels. No significant correlations were obtained between HRV data vs clinical data, BP and HR findings, and leptin levels in eating disorders. Body mass indices (BMI) (p<0.02), and leptin levels (p<0.04) correlated directly with BP values. Our data showed alterations of sympathovagal control of HRV in eating disorders. These changes were unrelated to body weight and BMI, diagnosis of AN or BN, and leptin levels despite the reported effects of leptin on the sympathetic activity.

The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts

The plant hormone abscisic acid (ABA) is released from glucose‐challenged human pancreatic β cells and stimulates insulin secretion. We investigated whether plasma ABA increased during oral and intravenous glucose tolerance tests (OGTTs and IVGTTs) in healthy human subjects. In all subjects undergoing OGTTs (n=8), plasma ABA increased over basal values (in a range from 2‐ to 9‐fold). A positive correlation was found between the ABA area under the curve (AUC) and the glucose AUC. In 4 out of 6 IVGTTs, little or no increase of ABA levels was observed. In the remaining subjects, the ABA increase was similar to that recorded during OGTTs. GLP‐1 stimulated ABA release from an insulinoma cell line and from human islets, by ~10‐ and 2‐fold in low and high glucose, respectively. Human adipose tissue also released ABA in response to high glucose. Nanomolar ABA stimulated glucose uptake, similarly to insulin, in rat L6 myoblasts and in murine 3T3‐L1 cells differentiated to adipocytes, by increasing GLUT‐4 translocation to the plasma membrane. Demonstration that a glucose load in humans is followed by a physiological rise of plasma ABA, which can enhance glucose uptake by adipose tissues and muscle cells, identifies ABA as a new mammalian hormone involved in glucose metabolism.—Bruzzone, S., Ameri, P., Briatore, L., Mannino, E., Basile, G., Andraghetti, G., Grozio, A., Magnone, M., Guida, L., Scarfì, S., Salis, A., Damonte, G., Sturla, L., Nencioni, A., Fenoglio, D., Fiory, F., Miele, C., Beguinot, F., Ruvolo, V., Bormioli, M., Colombo, G., Maggi, D., Murialdo, G., Cordera, R., De Flora, A., Zocchi, E. The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts. FASEB J. 26, 1251‐1260 (2012). www.fasebj.org

Interactions between vitamin D and IGF-I: from physiology to clinical practice.

The interplay between vitamin D and IGF‐I is complex and occurs at both endocrine and paracrine/autocrine levels. Vitamin D has been shown to increase circulating IGF‐I and IGFBP‐3, with the consistent finding of a positive correlation between vitamin D and IGF‐I serum values in population‐based cohorts of healthy subjects. The modulation of IGF‐I and IGFBP‐3 concentrations by vitamin D may impact recombinant human (rh) GH dosing for the treatment of GHD. It might also underlie some of the extra‐skeletal beneficial effects ascribed to vitamin D. On the other hand, IGF‐I stimulates renal production of 1,25‐dihydroxyvitamin D, which increases calcium and phosphate availability in the body and suppresses PTH secretion. This effect is responsible for an altered calcium–phosphate balance in uncontrolled acromegaly and might also account for the improvement in bone metabolism associated with rhGH treatment in patients with GHD. Data on the paracrine/autocrine vitamin D−IGF‐I interactions are abundant, but mostly not linked to one another. As a result, it is not possible to draw a comprehensive picture of the physiological and/or pathological interrelations between vitamin D, IGF‐I and IGF‐binding proteins (IGFBP) in different tissues. A potential role of vitamin D action is related to its association with carcinogenesis, a paradigm being breast cancer. Current evidence indicates that, in breast tumours, vitamin D modulates the IGF‐I/IGFBP ratio to decrease proliferation and increase apoptosis.

Relationship Between Fatty Degeneration of Thigh Muscles and Vitamin D Status in the Elderly: A Preliminary MRI Study

OBJECTIVE The purpose of this study was to study the relationship between fatty degeneration of thigh muscles and vitamin D status in elderly adults. SUBJECTS AND METHODS For six months, 121 patients 65 years old or older were evaluated. Myopathy, muscular impairment, and conditions influencing vitamin D status other than diet and sunlight were exclusion criteria. Twenty patients (10 men and 10 women; mean age, 77.6 years) underwent MRI. Thigh muscles were scanned from the hip to the knee with T1- and T2-weighted spin-echo sequences. Skeletal muscles were evaluated for fatty degeneration and atrophy from grade 0 to 3 (grade 0 = normal appearance, grade 3 = severe changes). The relationship between muscular fatty degeneration, 25-hydroxyvitamin D (25-OHD) levels, and scores on Tinetti scales for balance and gait were examined. RESULTS In the evaluation of the extensor muscles for fatty degeneration and atrophy, grade 0 was present in three patients (15%), grade 1 in 11 (55%), and grade 2 in six (30%). In the flexor muscles, grade 0 was found in one patient (5%), grade 1 in five (25%), and grade 2 in 14 (70%); grade 3 changes were not seen. Muscular fatty degeneration negatively correlated with 25-OHD levels (r = -0.50, p < 0.01) and the Tinetti scores (balance: r = -0.40, p < 0.05; gait: r = -0.50, p < 0.05). In 11 vitamin D-deficient patients (55%), there was selective complete atrophy of at least one thigh muscle. The gracilis and sartorius muscles were spared. CONCLUSION In elderly adults, fatty degeneration of thigh muscles was associated with vitamin D deficiency and impaired balance and gait. Selective complete fatty degeneration of single muscles was observed.

Somatostatin and dopamine receptor interaction in prostate and lung cancer cell lines

Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs). Recent studies on transfected cell lines have shown a ligand-induced formation of receptor dimers. The aim of this study is 1) to evaluate the role of specific ligands in modulating receptor interactions in the androgen-dependent prostate cancer cell line, LNCaP, and in the non-small cell lung cancer line, Calu-6, by co-immunoprecipitation and immunoblot; and 2) to correlate the antiproliferative effect of these compounds with their ability in modulating receptor interactions. In LNCaP, we have demonstrated the constitutive presence of sstr₁/sstr₂, sstr₂/sstr₅, sstr₅/dopamine (DA) type 2 receptor (D₂R), and sstr₂/D₂R dimers. BIM-23704 (sstr₁- and sstr₂-preferential compound) increased the co-immunoprecipitation of sstr₁/sstr₂ and significantly inhibited proliferation (-30.98%). BIM-23244 (sstr₂-sstr₅ selective agonist) significantly increased the co-immunoprecipitation of sstr₂/sstr₅, and induced a -41.36% inhibition of proliferation. BIM-23A760, a new somatostatin/DA chimeric agonist with a high affinity for sstr₂ and D₂R and a moderate affinity for sstr₅, significantly increased the sstr₅/D₂R and sstr₂/D₂R complexes and was the most powerful in inhibiting proliferation (-42.30%). The chimeric compound was also the most efficient in modulating receptor interaction in Calu-6, increasing the co-immunoprecipitation of D₂R/sstr₅ and inhibiting cell proliferation (-30.54%). However, behind BIM-23A760, BIM-53097 (D₂R-preferential compound) also significantly inhibited Calu-6 proliferation (-17.71%), suggesting a key role for D₂R in receptor cross talk and in controlling cell growth. Indeed, activation of monomeric receptors did not affect receptor co-immunoprecipitation, whereas cell proliferation was significantly inhibited when the receptors were synergistically activated. In conclusion, our data show a dynamic ligand-induced somatostatin and DA receptor interaction, which may be crucial for the antiproliferative effects of the new analogues.

Vitamin D increases circulating IGF1 in adults: potential implication for the treatment of GH deficiency

OBJECTIVES Previous studies suggested that vitamin D modulates circulating IGF1. We investigated this effect in adults and its clinical relevance in the management of GH deficiency (GHD). DESIGN AND METHODS IGF1 levels were prospectively measured before and after 12 weeks of treatment with oral vitamin D3 (5000 or 7000 IU/week) vs no intervention in 39 subjects 61.9±7.9 years old. The frequency of IGF1 values ≥50th age- and sex-specific percentile in relation to vitamin D status, as determined by the concentration of 25-hydroxyvitamin D (25(OH)D), was retrospectively assessed in 69 GHD patients (57.4±16.6 years) on stable hormone replacement and with 25(OH)D and IGF1 concurrently measured. RESULTS Treatment with 5000 and 7000 IU vitamin D3/week significantly raised 25(OH)D by 12.7±8.4 and 13.1±6.5 ng/ml respectively (both P<0.001 vs baseline). In the 7000 IU group, IGF1 levels also significantly increased by 31.3±36.7 ng/ml (P=0.01). Neither 25(OH)D nor IGF1 significantly varied in controls. IGF1 was ≥50th percentile more frequently in GHD patients with 25(OH)D levels ≥15 than <15 ng/ml (65.9 vs 40.0%, P<0.05). Logistic regression with adjustment for recombinant human GH (rhGH) dose, vitamin D supplements, gender, use of thyroid hormones, corticosteroids or estrogen/testosterone, and season revealed a significant positive association between ≥15 ng/ml 25(OH)D and IGF1 ≥50th percentile (OR 4.4, 95% CI 1.0-18.8, P<0.05). A significant negative correlation between 25(OH)D concentrations and rhGH dose was found after correcting for age and IGF1 (β -0.042, P<0.01), but not after further adjusting for sex, thyroid, adrenal or gonadal replacement, and season (β -0.037, P=0.06). CONCLUSIONS Vitamin D increases circulating IGF1 in adults. As a result, a better vitamin D status may ease the achievement of normal IGF1 values in GHD.

Relationship between vitamin D status and left ventricular geometry in a healthy population: results from the Baltimore Longitudinal Study of Aging

The effects of vitamin D on the heart have been studied in patients with cardiac disease, but not in healthy persons. We investigated the relation between vitamin D status and left ventricular (LV) structure and function in community‐dwelling subjects without heart disease.

Relationship between inter-arm difference in systolic blood pressure and arterial stiffness in community-dwelling older adults.

A significant inter‐arm difference in systolic blood pressure (IADSBP) has recently been associated with worse cardiovascular outcomes. The authors hypothesized that part of this association is mediated by arterial stiffness, and examined the relationship between significant IADSBP and carotid‐femoral pulse wave velocity (CF‐PWV) in a sample from the Baltimore Longitudinal Study of Aging. Of 1045 participants, 50 (4.8%) had an IADSBP ≥10 mm Hg at baseline, and 629 had completed data from ≥2 visits (for a total of 1704 visits during 8 years). CF‐PWV was significantly higher in patients with an IADSBP ≥10 mm Hg (7.3±1.9 vs 8.2±2, P=.002). Compared with others, patients with IADSBP ≥10 mm Hg also had higher body mass index, waist circumference, and triglycerides; higher prevalence of diabetes; and lower high‐density lipoprotein (HDL) cholesterol (P<.001 for all). A significant association with IADSBP ≥10 mm Hg was observed for CF‐PWV in both cross‐sectional (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.06–1.87; P=.01) and longitudinal (OR, 1.15; 95% CI, 1.03–1.29; P=.01) multivariate analyses. Female sex, Caucasian race, high body mass index (plus diabetes and low HDL cholesterol only cross‐sectionally) were other independent correlates of IADSBP ≥10 mm Hg. Significant IADSBP is associated with increased arterial stiffness in community‐dwelling older adults.

Wrist Injuries in Nonprofessional Tennis Players : Relationships With Different Grips

Background Recent advances in tennis teaching techniques have been applied in nonprofessional tennis players to develop a more effective play. Hits with enormous amount of top-spin and lower technical and physical training are responsible for most wrist injuries in nonprofessional tennis players. Hypothesis The use of different grips (Eastern, Western, semi-Western) determines the pattern of wrist injuries in nonprofessional tennis players. Study Design Cross-sectional study; Level of evidence, 3. Methods Between January 2006 and August 2007, we evaluated 370 nonprofessional division III and IV tennis players. The screening consisted of a questionnaire appropriately prepared to investigate wrist injuries. Medical records of players who reported a wrist injury were reviewed. Body mass index, years of practice, weekly hours of training, racket weight, grip (Eastern, Western and semi-Western), kind of strings, injury type, time out of competition, and therapy (medical or surgical) were recorded. Statistical analysis was performed to assess the association of different wrist injuries with these variables. Results A total of 320 players reported no injuries in their activity; 50 (13%) reported injuries to the wrist. Medical records of these players were reviewed, and 30 extensor carpi ulnaris lesions, 3 lesions of the extensor tendons, 5 injuries to the flexor carpi radialis, 6 de Quervain diseases, 5 triangular fibrocartilage lesions, and 1 intersection syndrome were found. Ulnar-sided injuries were more frequently associated with Western or semi-Western grips while radial-sided injuries were associated with Eastern grip (χ2 = 20.7; P < .001). Average time out of competition was 69 days; 4 players underwent surgery; the others received medical and rehabilitative therapy. No differences were observed regarding body mass index, years of practice, weekly hours of training, racket weight, and strings. Conclusion In nonprofessional tennis players with wrist injuries, different grips of the racket are related to the anatomical site of the lesion: Eastern grip with radial-side injuries and Western or semi-Western with ulnar-side injuries. Knowledge of this relationship may influence training, prevention, diagnosis, and therapy of wrist problems in nonprofessional tennis players.