Fabio Galetta

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.

A comparative study of the in vitro antioxidant activity of statins

BACKGROUND Treatment of hypercholesterolemia with statins is remarkably effective in cardiovascular prevention. This has led to the hypothesis that these drugs may act on the atherosclerotic plaque by mechanism(s) independent of the reduction of serum cholesterol levels. The aim of this study was to assess the total antioxidant activity of the most prescribed statins: fluvastatin, atorvastatin, pravastatin and simvastatin. METHODS We measured the in vitro antioxidant activity of statins as their ability to antagonize the oxidation of alpha-keto-gamma-methiolbutyric acid by both hydroxyl and peroxyl radicals. The results are expressed as Total Oxyradical Scavenging Capacity (TOSC) units. Uric acid and Trolox were used as the reference antioxidants. RESULTS The scavenging capacity towards hydroxyl radicals was highest for simvastatin (3375+/-112 U/mg), a value 270.2% higher (P<0.0001) compared to uric acid (reference antioxidant vs. hydroxyl radicals, 1249+/-71 U/mg). Among the tested statins, fluvastatin exhibited the highest anti-peroxyl radical antioxidant capacity (8755+/-187 U/mg) which appeared 50% lower (P<0.0001) compared to Trolox (reference antioxidant vs. peroxyl radicals, 17460+/-379 U/mg). CONCLUSIONS All the statins tested have intrinsic antioxidant activity with both anti-hydroxyl and peroxyl radical activity. Simvastatin was the most effective as an anti-hydroxyl radical antioxidant and fluvastatin as an anti-peroxyl radical antioxidant.

Heart rate variability and left ventricular diastolic function in anorexia nervosa

PURPOSE To investigate the cardiac effects of starvation in a group of adolescents with anorexia nervosa (AN). METHODS Twenty-five patients with AN (range 13-20 years), compared with 25 age-matched thin and 25 age-matched control women with body mass index > 20 Kg/m(2), underwent a complete clinical evaluation, including echocardiogram and 24-hour electrocardiogram monitoring to evaluate heart rate variability (HRV) indices. RESULTS Compared to both thin and control women, patients with AN had greater HRV time domain indices (SDNN: 246.5 +/- 32.4 vs. 170.4 +/- 24 ms and vs. 181 +/- 21.2 ms, p <.001), and in the frequency domain a lower LF/HF ratio (4.2 +/- 1.3 vs. 6.7 +/- 1.2 and vs. 6.8 +/- 1.3 ms, p <.001). AN patients showed reduced left ventricular mass with normal systolic function and typical diastolic patterns, characterized by a lower peak velocity transmitral flow in late diastole (peak A: 35.9 +/- 8.5 vs. 45.2 +/- 7.3 cm/sec and vs. 46.6 +/- 6.3 cm/sec, p <.01), a comparable peak velocity in early diastole (peak E: 92.7 +/- 12.1 vs. 83 +/- 6.2 and vs. 86.8 +/- 9.1 cm/sec, ns) and, subsequently, a greater E/A ratio (2.8 +/- 0.7 vs. 1.8 +/- 0.3 and vs. 1.9 +/- .5, p <.01) than thinness and control groups. Moreover, SDNN was also positively related to E/A ratio (r =.54, p <.01). CONCLUSIONS Our findings demonstrate a cardiovascular vagal hyperactivity in AN, which appears to influence the ventricular diastolic dynamics. HRV and diastolic function analysis may represent useful tools in monitoring anorexia-induced cardiac modifications.

Arterial stiffness, intima-media thickness and carotid artery fibrosis in patients with primary aldosteronism

Objectives To evaluate vascular wall structure and conduit artery stiffness in patients with primary aldosteronism. Methods This observational study, conducted in a University Hypertension Center, evaluated the carotid wall by 2-D ultrasonography and ultrasonic tissue characterization, and analyzed arterial stiffness by applanation tonometer. Twenty-three consecutive patients with primary aldosteronism, 24 matched patients with essential hypertension and 15 controls were studied. Intima-media thickness and corrected integrated backscatter signal of the carotid arteries were evaluated. Radial and femoral pulse wave velocity and aortic augmentation index were also investigated. Results Intima-media thickness in patients with essential hypertension (0.69 ± 0.03 mm) was higher (P < 0.04) than that in controls (0.59 ± 0.02 mm). This finding was more evident in primary aldosteronism patients (0.84 ± 0.03 mm), in whom intima-media thickness was greater than that in controls (P < 0.0001) or in patients with essential hypertension (P < 0.01). Similarly, corrected integrated backscatter signal in patients with essential hypertension (−23.6 ± 0.35 dB) was higher (P < 0.0001) than that in controls (−26.2 ± 0.44 dB), but it was even more elevated in patients with primary aldosteronism (−22.1 ± 0.46 dB), who showed greater corrected integrated backscatter signal than was the case in patients with essential hypertension (P < 0.009) or in controls (P < 0.0001). Femoral pulse wave velocity was higher in primary aldosteronism patients (10.8 ± 0.57 m/s) than in patients with essential hypertension (9.1 ± 0.34 m/s, P < 0.03) or in controls (7.1 ± 0.51 m/s, P < 0.0001). Femoral pulse wave velocity was lower in controls than in patients with essential hypertension (P < 0.0001). The same pattern was observed for radial pulse wave velocity. Aortic augmentation index was higher in primary aldosteronism patients (28.2 ± 2.1%) than in patients with essential hypertension (26.0 ± 1.8%) or in controls (16.8 ± 2.0%, P < 0.001). Patients with essential hypertension likewise exhibited higher aortic augmentation index than controls (P < 0.001). Conclusion Aldosterone excess is responsible per se for vascular morphological (wall thickening and carotid artery fibrosis) and functional (central stiffness) damage.

Effects of age and physical fitness on microcirculatory function

Sedentary aging is associated with endothelial dysfunction and nitric oxide (NO) impairment. The aim of the present study was to assess the effects of regular physical exercise on nitrite/nitrate (NOx) concentrations and microcirculatory function in older men compared with young individuals. We measured NOx plasma concentrations and baseline and stimulated skin blood flow (SBF) by laser Doppler flowmetry in 39 male athletes [range, 22-72 years; maximal oxygen consumption (VO2max), 60.0 +/- 4.7 ml.min(-1).kg of body weight(-1) (mean +/- S.D.)] and 45 age- and sex-matched sedentary controls (VO2max, 38.0 +/- 7.1 ml.min(-1).kg of body weight(-1)). NOx concentrations were higher in athletes than in controls (50.4 +/- 16.3 compared with 39.0 +/- 15.4 micromol/l; P<0.005), whereas baseline SBF was comparable. Hand SBF after heating and ischaemia and foot SBF after heating were higher in athletes (P<0.0001) than in controls. By comparing the lowest and the highest tertile of age, sedentary young subjects had higher NOx concentrations than sedentary older subjects (43.3 +/- 13.4 compared with 31.8 +/- 12.2 micromol/l respectively; P<0.05). Exercise abolished this difference (49.1 +/- 9.6 micromol/l for young subjects and 52.1 +/- 11.5 micromol/l for older subjects; not significant). Resting SBF was similar in all the subgroups, but stimulated SBFs were lower in both subgroups of untrained compared with trained subjects. NOx concentrations were positively correlated with VO2max (r=0.46, P<0.001). Stimulated SBFs were correlated with NOx (r>0.30, P<0.05). These findings show that chronic exercise may improve endothelial function in older (and young) men, probably by increasing NO availability.

Potassium Removal Increases the QTc Interval Dispersion during Hemodialysis

This study was planned to clarify the mechanism(s) by which hemodialysis increases the QTc dispersion, a marker of risk of ventricular arrhythmias. To this aim, 10 uremic patients, without any relevant heart diseases, underwent two different types of hemodialysis schedules. In the first, 1 h of isolated high rate ultrafiltration preceded the standard diffusive procedure. In the second, during the first hour of standard bicarbonate hemodialysis, the decrease of plasma potassium concentration was prevented by increasing K+ concentration in the dialysate, according to its pre dialysis plasma levels. During the high rate ultrafiltration period, together with ECG signs of increased sympathetic nervous system activity and catecholamines secretion, the QTc dispersion did not change significantly. Instead, an evident increment was observed 1 h after the start of the diffusive hemodialysis, then slowly progressing until the end of the dialysis and finally returning to the pre dialysis values within 2 h after the end of the session. To the contrary, the increase of the QTc dispersion was totally blunted during a standard hemodialysis procedure in absence of plasma K+ decrease, but appeared again when the K+ dialysate fluid concentration was restored to 2 mmol/l. This study provides evidence that the increase of QTc dispersion occurring on hemodialysis is mainly related to the diffusive process, more precisely to the K+ removal. This is one more reason to focus attention on K+ removal rate especially when hemodialysis treatment is given in uremics affected by cardiac diseases with high risk of arrhythmias.

Thyroid hormones and the cardiovascular system: Pathophysiology and interventions

Thyroid dysfunction, however mild, can significantly affect the cardiovascular (CV) system. The effects of thyroid hormones may be viewed as genomic and non-genomic, with the former occurring over a longer time scale and both affecting structural and functional proteins in CV tissue. As the interplay between thyroid function and the CV system becomes elucidated, particularly in the context of a system biology approach, the heart failure phenotype is better understood. Symptomatology is related to disturbance in inotropic and chronotropic function. Moreover, biochemical changes reflected by thyroid function testing with the non-thyroidal illness syndrome can prognosticate and guide therapy in heart failure. In addition, empiric treatment with thyroid hormone analogues or T3 represent emergent and highly controversial interventions.

Oxidative stress biomarkers in mitochondrial myopathies, basally and after cysteine donor supplementation

Mitochondrial diseases are due to impairment of the mitochondrial respiratory chain. A plausible pathogenic mechanism leading to cellular dysfunction and phenotypic expression is oxidative stress, but there are surprisingly few clinical studies on this subject. Glutathione (GSH) deficiency has been reported in mitochondrial diseases, and the biosynthesis of glutathione depends on cysteine availability. We have examined oxidative stress biomarkers [advanced oxidation protein products (AOPP) and ferric reducing antioxidant power (FRAP)] in blood samples from 27 patients and 42 controls. AOPP levels were greater in patients than in controls (P value <0.00001). Therefore, we performed a double-blind cross-over study to evaluate if 30-day supplementation with a whey-based cysteine donor could modify these markers, reduce lactate concentration during aerobic exercise, or enhance muscular strength and quality of life. Treatment did not modify lactate concentration, clinical scale (MRC) or quality of life (SF-36), but significantly reduced oxidative stress levels. Our findings reinforce the notions that in mitochondrial diseases oxidative stress is important and can be reduced by administration of a cysteine donor. Oxidative stress biomarkers may be useful to detect redox imbalance in mitochondrial diseases and to provide non-invasive tools to monitor disease status.

Effect of Hemodialysis on the Dispersion of the QTc Interval

The QTc dispersion reflects the underlying regional heterogeneity of the recovery of the ventricular excitability, thereby it is considered as a novel marker of risk of ventricular arrhythmias. Because a higher incidence of ventricular arrhythmias is described during and after hemodialysis, the aim of this study has been to evaluate the QTc dispersion before and after uncomplicated hemodialysis session. Twenty chronic uremics without heart failure, ischemic heart disease or dialysis hypotension were selected. The QTc dispersion was determined as the difference between the longer and the shorter QTc interval measured on a 12-lead electrocardiogram. Following the hemodialysis session, the QTc dispersion increased from 30 ± 9 to 54 ± 17 ms (p < 0.001) associated with the expected reduction of potassium and magnesium and with the increase of extracellular calcium concentration. However, no correlation has been observed between the QTc dispersion increase and the degree of the intradialytic changes of plasma electrolytes, blood pressure or body weight. In summary, the hemodialysis treatment per se does induce an increase of the QTc dispersion, likely due to the rapid changes of electrolyte plasma concentrations. This can potentially contribute to the arrhythmogenic effect of the hemodialysis procedure, reflecting an enhanced regional heterogeneity of ventricular repolarization. The clinical importance of the increase of QTc dispersion as risk factor of ventricular arrhythmias, particularly in hemodialyzed patients suffering from ischemic or hypertrophic heart diseases, should be the matter of further investigations.

High Values of CXCL10 Serum Levels in Mixed Cryoglobulinemia Associated With Hepatitis C Infection

OBJECTIVES:No study has evaluated circulating CXCL10 in patients with mixed cryoglobulinemia (MC) and hepatitis C virus (HCV) chronic infection. The aim of this study is to measure inteferon-inducible protein 10 (CXCL10/IP-10), interferon-gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) (Th1 cytokines) in a series of cryoglobulinemic patients and to correlate this parameter to the clinical phenotype.METHODS:Serum CXCL10, IFN-gamma, and TNF-alpha were assayed in 102 patients with hepatitis C-associated cryoglobulinemia (MC + HCV), in 102 sex- and age-matched patients with type C chronic hepatitis without cryoglobulinemia (HCV+), and in 102 sex- and age-matched controls.RESULTS:Cryoglobulinemic patients showed significantly higher mean CXCL10 serum levels than controls (P < 0.0001) or HCV+ patients (P < 0.0001) (397 ± 132 pg/mL, 92 ± 53 pg/mL, 280 ± 149 pg/mL, respectively). Moreover, CXCL10 was significantly increased in 30 cryoglobulinemic patients with active vasculitis compared to those without it (460 ± 104 pg/mL vs 369 ± 139 pg/mL, respectively; P < 0.001). Both groups of MC + HCV patients with or without active vasculitis had serum CXCL10 significantly higher than HCV+ patients (P < 0.001, P= 0.02, respectively). IFN-gamma levels were not significantly different in MC + HCV than in HCV+ patients or controls. Serum TNF-alpha levels were significantly higher in MC + HCV than in HCV+ patients or controls (median [interquartile range]: 12.0 [9.8], 5.7 [5.4], 1.3 [2.1] pg/mL, respectively; P < 0.0001).CONCLUSIONS:The study demonstrates high CXCL10 and TNF-alpha serum levels in patients with hepatitis C-associated cryoglobulinemia. Moreover, in MC + HCV patients, increased CXCL10 levels were significantly associated with the presence of active vasculitis.