Non-thyroidal illness syndrome in chronic diseases: role of irisin as modulator of antioxidants.

OBJECTIVE: Non-thyroidal-illness syndrome (NTIS) refers to condition found in chronic diseases that is an adaptive mechanism. However, oxidative stress is related to NTIS in a vicious circle, due to deiodinases alteration and negative effects of low T3 on antioxidant levels or activity. Muscle is one of the main targets of thyroid hormones and it can secrete a myokine named irisin, which is able to induce the browning of white adipose tissue, energy expenditure and protect against insulin resistance. Inconclusive data have been reported about irisin role in chronic diseases. Moreover, no correlation with antioxidants has been investigated. Therefore, we performed a case-control study with the primary endpoint to evaluate irisin levels in two models of NTIS, such as chronic heart failure (CHF) and chronic kidney disease (CKD) during haemodialytic treatment. The secondary endpoint was the correlation with total antioxidant capacity (TAC) to establish a possible role of irisin in the modulation of antioxidant systems. PATIENTS AND METHODS: Three groups of subjects were enrolled. Group A included CHF patients (n=18; aged 70.22 ± 2.78 ys; BMI ± 27.75 ± 1.28 kg/m2); Group B included CKD patients (n=29; aged 67.03 ± 2.64; BMI 24.53 ± 1.01); finally, 11 normal subjects (Group C) have been enrolled as controls. Irisin has been evaluated by ELISA method and Total Antioxidant Capacity (TAC) by spectrophotometric method. RESULTS: Irisin was significantly higher in Group B vs. A and C groups (Mean ± SEM: 20.18 ± 0.61 ng/ml vs. 2.77 ± 0.77 and 13.06 ± 0.56, respectively; p<0.05); a significant correlation between irisin and TAC was observed in group B. CONCLUSIONS: These preliminary data suggest a possible role of irisin in the modulation of antioxidants in two chronic syndromes with low T3 (i.e., CHF and CKD) with differential pattern in these two models studied. Further insights are needed to confirm this pilot study, which could be the basis for a longitudinal investigation, to assess a prognostic role of irisin with possible therapeutic implications.

Hormonal deficiencies in heart failure with preserved ejection fraction: prevalence and impact on diastolic dysfunction: a pilot study.

OBJECTIVE: In heart failure with reduced ejection fraction, catabolic mechanisms have a strong negative impact on mortality and morbidity. The relationship between anabolic hormonal deficiency, thyroid function, and heart failure with preserved ejection fraction (HFpEF) has still been poorly investigated. Therefore, we aimed to define the multi-hormonal deficiency prevalence in HFpEF patients and the relationships between hormonal deficiency and echocardiographic indexes. PATIENTS AND METHODS: Plasma levels of N-terminal pro-brain natriuretic peptide, fasting glucose, thyroid-stimulating hormone, free triiodothyronine (T3), free thyroxine, insulin-like growth factor-1, dehydroepiandrosterone-sulfate (DHEA-S), total testosterone (only in male subjects) in 40 patients with HFpEF were evaluated. An echocardiographic evaluation was performed. RESULTS: One (2.5%) patient (2.5%) had no hormonal deficiencies; 8 (20%) patients had deficits of one hormone, 18 patients (45%) of two axes, 12 patients (30%) of three axes, and one patient (2.5%) of all four axes. Among them, 97.5% had DHEA-S deficiency, 67.5% IGF-1 deficiency, 37% testosterone deficiency, 22.5% a "Low T3 syndrome", and 20% subclinical hypothyroidism. Patients with IGF-1 deficit showed higher left atrial volume values, systolic pulmonary artery pressure (SPAP), tricuspid peak velocity (TPV), and lower tricuspid annular plane systolic excursion (TAPSE) and TAPSE/SPAP ratio values. Patients with testosterone deficiency had higher SPAP and TPV. Patients with low T3 syndrome had higher value of right ventricular mid cavity diameter. Hormonal dysfunction was independent from the presence of comorbidities and no difference between male and female subjects was noted. CONCLUSIONS: Multi-hormonal deficiencies are associated with right ventricular dysfunction and diastolic dysfunction in patients with HFpEF.

Oxidative stress as a possible mechanism underlying multi-hormonal deficiency in chronic heart failure.

OBJECTIVE: Chronic Heart Failure (CHF) is associated with multi-hormonal derangement depicting a prevalence of catabolic vs. anabolic axes. Moreover, thyroid adaption is characterized by the reduced conversion of thyroxine to the active hormone triiodothyronine. On the other hand, hormones modulate synthesis and utilization of antioxidant systems. Therefore, hormonal failure can cause unbalance between reactive radical species and the defenses, resulting in oxidative stress (OS). OS is well described in CHF, but the relationship with the hormonal picture is not entirely known. In the present review, we firstly analyze the mechanisms of ROS production in the heart, discussing animal and human studies, and focusing on new discovered protective mechanisms such as sirtuins and fibroblast growth factor 21 (FGF21). The second section is dedicated to the role of main anabolic axes influencing antioxidant systems. Finally, we present some data supporting the hypothesis that OS could be the link between hormonal derangement and clinical outcome of CHF.

Anthracycline and trastuzumab-induced cardiotoxicity in breast cancer.

OBJECTIVE: Breast cancer is the most common cancer among women. In the last twenty years early diagnosis, neoadjuvant and adjuvant systemic treatment that targeted to specific molecular targets have significantly reduced the mortality from breast cancer. However, the increase in survival has allowed to observe the cardiotoxic effects of anticancer therapy and increased mortality from cardiovascular causes, resulting in a large literature where experts try to identify the correct management of this critical problem. Even thought the increased attention in this field, many questions have not yet answers and new studies are needed. MATERIALS AND METHODS: We conducted a broad search of the English-language literature in Medline using the following search terms: cardiotoxicity, anthracyclines, trastuzumab, breast cancer, left ventricular dysfunction, heart failure. A manual examination of the articles found has been performed. RESULTS: We provide a comprehensive assessment of the current knowledge about cardiotoxicity induced by anthracycline plus trastuzumab in women affected by breast cancer. CONCLUSIONS: Early identification and prompt treatment of subclinical cardiotoxicity may improve cardiologic prognosis of these patients and may allow oncologists to avoid withdrawal of chemotherapy. That is why it becomes always more important the creation of multidisciplinary teams where cardiologists and oncologists work together to ensure optimal care to oncologic patients treated with cardiotoxic agents.

Molecular mechanisms of diabetes reversibility after bariatric surgery.

OBJECTIVE: Insulin resistance is a strong biological marker of both obesity and type 2 diabetes. Abnormal fat deposition within skeletal muscle has been identified as a mechanism of obesity-associated insulin resistance. Biliopancreatic diversion (BPD), inducing a massive lipid malabsorption, leads to a reversion of type 2 diabetes. To elucidate the mechanisms of diabetes reversibility, the expression of genes involved in glucose and free fatty acids (FFAs) metabolism was investigated in skeletal muscle biopsies from obese, type 2 diabetic subjects. Peripheral insulin sensitivity and insulin secretion was also measured. SUBJECTS: Eight Caucasian obese diabetic patients (BMI 52.1+/-1.85 kg/m(2)) were studied before and 3 years after BPD. MEASUREMENTS: The mRNA levels were estimated by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR), insulin sensitivity by the euglycemic-hyperinsulinemic clamp and insulin secretion using a model describing the relationship between insulin secretion and glucose concentration. RESULTS: Whole-body glucose uptake (M), normalized by fat-free mass, significantly increased in post-obese subjects (P<0.0001). Total insulin output decreased (P<0.05) in association with a significant improvement of beta-cells glucose sensitivity (P<0.05). mRNA levels of FABP3 (P<0.05), FACL (P<0.05), ACC2 (P<0.05), HKII (P<0.05) and PDK4 (P<0.05) were significantly decreased, while SREBP1c mRNA increased (P<0.05) after BPD. CONCLUSION: Reversibility of type 2 diabetes after BPD is dependent on the improvement of skeletal muscle insulin sensitivity, mediated by changes in the expression of genes regulating glucose and fatty acid metabolism in response to nutrient availability.

Subclinical hepatic encephalopathy: role of tryptophan binding to albumin and the competition with indole-3-acetic acid.

BACKGROUND: The role of tryptophan (TRY) and its metabolites in the pathogenesis of hepatic encephalopathy is conflicting. The aim of the present study is to investigate in posthepatitis cirrhotic patients with encephalopathy the serum levels of TRY and those of its metabolite indole-3-acetic acid, as well as TRY binding curve to serum albumin and the competition with indole-3-acetic acid. The presence of a relationship between encephalopathy severity and circulating free TRY was also investigated. METHODS: Serum TRY and indole-3-acetic acid were analyzed by HPLC; binding of TRY to serum albumin and the competition with indole-3-acetic acid was studied by equilibrium dialysis. RESULTS: Serum-free TRY was significantly higher in cirrhotic patients (43.33 +/- 14.70 vs 28.87 +/- 8.77 mumol/L, P = 0.02). The binding capacity of albumin was reduced in cirrhotics and further decreased by the addition of indole-3-acetic (K = 6.63 +/- 0.97 x 10(3) mol/L-1, gamma = 1.16 +/- 0.45 x 10(2) mol/L-1 in normal sera vs K = 1.04 +/- 0.20 x 10(3) mol/L-1, gamma = 1.91 +/- 0.92 10(2) mol/L-1 in cirrhotic sera). A multivariate analysis showed that among the psychometric tests the only independent predictor of serum levels of free TRY was the Block Design (R2 = 0.94, B = 0.16 +/- 0.01, beta = 0.97; P < 0.0001). CONCLUSIONS: A high percent ratio of free/total TRY and indoleacetic acid (IAA) was found in cirrhotic patients with hepatic encephalopathy. The concentrations of serum-free IAA and TRY correlated with the degree of subclinical encephalopathy, suggesting a role of these compounds in the development of mental derangement in liver cirrhosis.

Serum leptin levels in post-hepatitis liver cirrhosis.

BACKGROUND/AIMS: Little information is available on the involvement of leptin in clinical conditions associated with malnutrition, such as liver cirrhosis. The behaviour of serum leptin in patients with different Child-Pugh score, post-hepatitis liver cirrhosis and insulin sensitivity has therefore been investigated and compared with that in alcoholic Child C patients. METHODS: Sixty-four patients, aged 51 to 62 years, with different degrees of post-hepatitis cirrhosis or Child C alcoholic cirrhosis were compared with 15 age-matched control subjects. Body composition was estimated by skinfold thickness. Serum leptin, glucose and insulin were assayed. RESULTS: In post-hepatitis patients a significant reduction in leptin levels was observed as the Child-Pugh score worsened (men: 2.94+/-1.61 in Child C vs 6.78+/-2.49 ng/ml in controls, p<0.001; women: 4.14+/-0.66 in Child C vs 16.16+/-3.90 ng/ml in controls, p<0.02). Conversely, only the men with alcoholic liver cirrhosis showed a significant difference in leptin concentration compared to controls (8.5+/-2.1 vs 16.4+/-7.9 kg, p<0.05). In particular, Child C, alcoholic cirrhotic women had a significantly (p=0.03) higher level of leptin than post-hepatitis matched women. A positive correlation was observed between leptin and fat mass (men R2=0.59, p<0.0001 and women R2=0.65, p<0.0001). While fasting levels of serum leptin correlated significantly with insulin concentrations in controls, a similar relationship was not observed in the cirrhotic population, which displayed higher insulin concentrations than controls. CONCLUSIONS: In contrast to findings in alcoholic cirrhotic women, low leptin values in post-hepatitis cirrhotic patients mainly represent the expression of a reduced fat mass.

Pharmacokinetics of sebacic acid in rats.

The pharmacokinetics of disodium sebacate (Sb) was studied in Wistar rats of both sexes. Sebacate was administered either as intra-peritoneal (i.p.) bolus (six doses ranging from 10 mg to 320 mg) or as oral bolus (two doses: 80 and 160 mg). Plasma and urinary concentrations of Sb and urinary concentrations of Sb and its products of beta-oxidation (suberic and adipic acids) were measured by an improved method using gas-liquid chromatography/mass-spectrometry. A single compartment with two linear elimination routes was selected after no increase in significance was shown by an additional compartment and after a saturable mechanism was found to be unsuitable. Both renal and non-renal elimination parameters were obtained by Marquardt non linear fitting of plasma concentrations together with urinary elimination. The data reported are calculated from the analysis on the whole population of rats and referred to an average body weight (bw) of 100 g. The Sb half-time was 31.5 min. The tissue elimination rate was 0.0122 min-1. The overall volume of distribution was found to be 26.817 ml/100 g bw. The renal clearance was 0.291 ml/min/100 g of bw, which is much less than the value of GFR reported in literature (about 1 ml/min/100 g bw), suggesting the presence of Sb reabsorption from the ultrafiltrate. The value of Sb renal clearance was found to be a concentration-independent function, suggesting the presence of a passive back-diffusion. The relative bioavailability of the oral form compared to the i.p. form was 69.09%, showing a good absorption of the drug.

Doppler ultrasound of blood flow velocities in ophthalmic and central retinal arteries during the early neonatal period.

PURPOSE: To obtain standard values of blood flow velocity in the ophthalmic artery and central retinal artery in the neonatal period and to compare blood flow velocity of orbital vessels with that of the anterior cerebral artery and middle cerebral artery. METHODS: Forty-five healthy neonates (gestational age, 39.2 +/- 1.2 weeks; birth weight, 3,210 +/- 567 g) on the first and third postnatal days (90 eyes each time) and on the fifth day of life (34 eyes) were included in a clinical trial. A duplex scanner with mechanical sector probe was used for measuring blood flow velocity in the ophthalmic artery, central retinal artery, anterior cerebral artery, and middle cerebral artery. A nominal imaging frequency of 7.5 MHz, a transmitted Doppler frequency of 5 MHz, and a wall filter setting of 50 Hz were used in each case. Systolic, end-diastolic, and mean-enveloped velocities were measured for the studied vessels and the resistance and pulsatility indices were calculated. RESULTS: On the first postnatal day, blood flow velocities and indices in the ophthalmic artery were systolic 14 +/- 2.4 cm/sec, end-diastolic 3.8 +/- 0.6 cm/sec, mean-enveloped 7.3 +/- 1.3 cm/sec, resistance index 0.73 +/- 0.03, and pulsatility index 1.5 +/- 0.2. Central retinal artery blood flow velocities and indices were systolic 8.7 +/- 1.8 cm/sec, end-diastolic 2.7 +/- 0.7 cm/sec, mean-enveloped 5.0 +/- 1.1 cm/sec, resistance index 0.70 +/- 0.04, and pulsatility index 1.3 +/- 0.1. There were no significant differences in ophthalmic artery and central retinal artery flow velocities between right and left eyes. Doppler values of the central retinal artery were significantly lower (P = .0005) than those of the ophthalmic artery for each day studied. The Doppler data for the central retinal artery and ophthalmic artery were significantly lower (from P = .005 to .0001) than those observed in the anterior cerebral artery and middle cerebral artery at the same postnatal age. No significant differences in flow variables were found in the central retinal artery and ophthalmic artery from the first to third day, whereas blood flow velocities in the anterior cerebral artery and middle cerebral artery increased significantly (P = .01 to .0001) from day 1 to day 3. On the fifth day of life a significant increase in blood flow velocities and indices was observed in the ophthalmic artery, whereas only systolic velocity significantly increased in the central retinal artery. CONCLUSIONS: We report blood flow data of the ophthalmic artery and central retinal artery in healthy neonates and suggest that a delay of arterial blood flow changes occurs for the ophthalmic artery and central retinal artery with respect to the anterior cerebral artery and middle cerebral artery in the early prenatal period.

Safe removal of the radial artery for myocardial revascularization: a Doppler study to prevent ischemic complications to the hand.

Radial artery harvesting has recently been reintroduced for myocardial revascularization. Harvesting the radial artery may jeopardize the vascularization of the hand; cautious selection of candidates must therefore be pursued. The study involved 188 consecutive patients. We verified the patency of the upper limb's arteries and the adequacy of the ulnar supply by static and dynamic Doppler evaluations. The use of the radial artery was contraindicated in 14 cases (three for stenosis of the subclavian artery and 11 for inadequate collateralization). One hundred patients were operated on with the radial artery used as a graft; the remaining 74 patients had a different conduit placed. The vascularization of the hand was restudied within 10 days in all patients who underwent operation; in 63 patients, it was studied again at 1 year. The early Doppler examination showed significant increase in blood flow velocities in the ulnar artery, with a flow redistribution in the common digital palmar arteries (decreased in the first and increased in the second and the third). The late Doppler examination showed superimposable findings. No local ischemic complications were observed. We conclude that Doppler study is a useful tool in preoperative screening of candidates for radial artery harvesting for myocardial revascularization.

New prospects for the treatment of Raynaud's phenomenon using a serotoninergic S2 receptor antagonist (ketanserin) and stable derivatives of prostacyclin.

The authors propose a promising new therapy for the treatment of Raynaud's phenomenon, with parenteral prostacyclin (carbaprostacyclin) and a serotonergic S2-receptor antagonist (ketanserin) given orally. They studied 31 patients, 22 treated with ketanserin and carbaprostacyclin, 9 with carbaprostacyclin alone. Both groups demonstrated successful results and a significant improvement in measurements performed by photoplethysmography and transcutaneous pulse oximetry.

A comparison of the assessment of mitral valve area by continuous wave Doppler and by cross sectional echocardiography.

Transmitral pressure half time (PHT) was assessed by continuous wave Doppler in 44 patients with rheumatic mitral valve stenosis (14, pure mitral valve stenosis; 15, combined mitral stenosis and regurgitation; and 15 with associated aortic valve regurgitation). The mitral valve area, derived from transmitral pressure half time by the formula 220/pressure half time, was compared with that estimated by cross sectional echocardiography. The transmitral pressure half time correlated well with the mitral valve area estimated by cross sectional echocardiography. The correlation between pressure half time and the cross sectional echocardiographic mitral valve area was also good for patients with pure mitral stenosis and for those with associated mitral or aortic regurgitation. The regression coefficients in the three groups of patients were significantly different. Nevertheless, a transmitral pressure half time of 175 ms correctly identified 20 of 21 patients with cross sectional echocardiographic mitral valve areas less than 1.5 cm2. There were no false positives. The Doppler formula significantly underestimated the mitral valve area determined by cross sectional echocardiography by 28(9)% in 19 patients with an echocardiographic area greater than 2 cm2 and by 14.8 (8)% in 25 patients with area of less than 2 cm2. In thirteen patients with pure mitral valve stenosis Gorlin's formula was used to calculate the mitral valve area. This was overestimated by cross sectional echocardiography by 0.16 (0.19) cm2 and underestimated by Doppler by 0.13 (0.12) cm2. Continuous wave Doppler underestimated the echocardiographic mitral valve area in patients with mild mitral stenosis. The Doppler formula mitral valve area = 220/pressure half time was more accurate in predicting functional (haemodynamic) than anatomical (echocardiographic) mitral valve area.

Pulsed Doppler echocardiographic analysis of mitral regurgitation after myocardial infarction.

In 72 patients with previous myocardial infarction (MI), mitral regurgitation (MR) was assessed by pulsed-wave Doppler echocardiography and compared with physical and 2-dimensional echocardiographic findings. MR was found by Doppler in 29 of 42 patients (62%) with anterior MI, 11 of 30 (37%) with inferior MI (p less than 0.01) and in none of 20 normal control subjects. MR was more frequent in patients who underwent Doppler study 3 months after MI than in those who underwent Doppler at discharge (anterior MI = 83% vs 50%, p less than 0.01; inferior MI = 47% vs 27%, p = not significant). Of 15 patients who underwent Doppler studies both times, 3 (all with anterior MI) had MR only on the second study. Of the patients with Doppler MR, 12 of 27 (44%) with a left ventricular (LV) ejection fraction (EF) greater than 30% and 1 of 13 (8%) with an EF of 30% or less (p less than 0.01) had an MR systolic murmur. Mitral prolapse or eversion and papillary muscle fibrosis were infrequent in MI patients, whether or not Doppler MR was present. The degree of Doppler MR correlated with EF (r = -0.61), LV systolic volume (r = 0.47), and systolic and diastolic mitral anulus circumference (r = 0.52 and 0.51, respectively). Doppler MR was present in 24 of 28 patients (86%) with an EF of 40% or less and in 16 of 44 (36%) with EF more than 40% (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)