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Aims The aim is to investigate autonomic nervous system imbalance in hypertrophic cardiomyopathy (HCM) by combining echocardiographic morphological and functional parameters with the analysis of the autonomic responses to orthostatic stress. Methods A 10-min tilting test and a transthoracic echocardiogram focused on ventricular septal systolic (S wave) and diastolic function (isovolumic relaxation time) were performed. Low frequency on high frequency ratio (LF/HF) and RR variation (variation of beat to beat intervals) in response to passive orthostatism were used as measures of sympathetic reflex activation [delta LF/HF (D-LF/HF) and delta RR (DRR), respectively]. Brain natriuretic peptide was measured. Results A total of 50 HCM patients were categorized in two groups: D-LF/HF more than 0 (group 1, sympathetic response) and D-LF/HF 0 or less (group 2, parasympathetic response). Patients in group 2 had higher New York Heart Association class, a more frequent history of atrial fibrillation (38 versus 9% P = 0.04) or syncope (46 versus 12% P = 0.01) and an increased septal isovolumic relaxation time (122 versus 82 ms P = 0.02). The same categorization was made according to lowest quartile DRR (DRR at least 23 ms, group 1: sympathetic response; DRR less than 23 ms, group 2: parasympathetic response). In group 2, patients were older, with advanced New York Heart Association class and higher history of atrial fibrillation. Conclusions Autonomic response to passive orthostatism in HCM appears correlated with specific functional features of the hypertrophic heart. Altered neural afferent traffic from the localized area of segmental hypertrophy resulted in autonomic changes with a blunted sympathetic response, and an inappropriate vagal activation, especially in patients with history of atrial fibrillation or syncope.

Background--Acute exposure to high-altitude hypobaric hypoxia induces a blood pressure rise in hypertensive humans, both at rest and during exercise. It is unclear whether this phenomenon reflects specific blood pressure hyperreactivity or rather an upward shift of blood pressure levels. We aimed at evaluating the extent and rate of blood pressure rise during exercise in hypertensive subjects acutely exposed to high altitude, and how these alterations can be counterbalanced by antihypertensive treatment. Methods and Results--Fifty-five subjects with mild hypertension, double-blindly randomized to placebo or to a fixed-dose combination of an angiotensin-receptor blocker (telmisartan 80 mg) and a calcium-channel blocker (nifedipine slow release 30 mg), performed a cardiopulmonary exercise test at sea level and after the first night's stay at 3260 m altitude. High-altitude exposure caused both an 8 mm Hg upward shift (P < 0.01) and a 0.4 mm Hg/mL/kg per minute steepening (P < 0.05) of the systolic blood pressure/oxygen consumption relationship during exercise, independent of treatment. Telmisartan/nifedipine did not modify blood pressure reactivity to exercise (blood pressure/oxygen consumption slope), but downward shifted (P < 0.001) the relationship between systolic blood pressure and oxygen consumption by 26 mm Hg, both at sea level and at altitude. Muscle oxygen delivery was not influenced by altitude exposure but was higher on telmisartan/nifedipine than on placebo (P < 0.01). Conclusions--In hypertensive subjects exposed to high altitude, we observed a hypoxia-driven upward shift and steepening of the blood pressure response to exercise. The effect of the combination of telmisartan/nifedipine slow release outweighed these changes and was associated with better muscle oxygen delivery.

Objectives In patients with abnormal left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI), cardiac rehabilitation with physical training prevents cardiac remodelling. To define the role of rehabilitation in the recovery of ventricular function in less severe cases, we studied its effects on more refined indexes of left ventricular function in uncomplicated, low-risk patients. Methods and results Fifty-five patients underwent percutaneous coronary revascularization after uncomplicated first AMI. Thirty-four started cardiac rehabilitation with counselling and physical training; 21 patients did not train, followed a counselling program and were taken as controls. Echocardiography was performed at baseline, after rehabilitation or counselling program and at six months follow-up. We measured: global strain (GS%) with speckle tracking analysis, E/e’ by tissue Doppler imaging (TDI), left ventricular elastance (K LV ) from the deceleration time (DT), LVEF, systolic and diastolic volumes, wall motion score index (WMSI). At baseline, groups had similar GS%, K LV , LVEF, DT, E/e’, systolic and diastolic volumes, WMSI. Rehabilitation increased peak VO 2 by 18% (P < 0.05) and improved GS%, K LV , LVEF, E/e’ and WMSI (P < 0.02) that were unchanged in controls. The improvement persisted at six months. Conclusions After a first uncomplicated AMI, abnormalities of left systolic and diastolic ventricular function may be present persisting over time despite a normal LVEF, which are fully reverted by cardiac rehabilitation.

This randomized, double-blind, placebo-controlled study was designed to explore the effects of exposure to very high altitude hypoxia on vascular wall properties and to clarify the role of renin-angiotensin-aldosterone system inhibition on these vascular changes. Forty-seven healthy subjects were included in this study: 22 randomized to telmisartan (age, 40.3±10.8 years; 7 women) and 25 to placebo (age, 39.3±9.8 years; 7 women). Tests were performed at sea level, pre- and post-treatment, during acute exposure to 3400 and 5400-m altitude (Mt. Everest Base Camp), and after 2 weeks, at 5400 m. The effects of hypobaric hypoxia on mechanical properties of large arteries were assessed by applanation tonometry, measuring carotid-femoral pulse wave velocity, analyzing arterial pulse waveforms, and evaluating subendocardial oxygen supply/demand index. No differences in hemodynamic changes during acute and prolonged exposure to 5400-m altitude were found between telmisartan and placebo groups. Aortic pulse wave velocity significantly increased with altitude (P<0.001) from 7.41±1.25 m/s at sea level to 7.70±1.13 m/s at 3400 m and to 8.52±1.59 m/s at arrival at 5400 m (P<0.0001), remaining elevated during prolonged exposure to this altitude (8.41±1.12 m/s; P<0.0001). Subendocardial oxygen supply/demand index significantly decreased with acute exposure to 3400 m: from 1.72±0.30 m/s at sea level to 1.41±0.27 m/s at 3400 m (P<0.001), remaining significantly although slightly less reduced after reaching 5400 m (1.52±0.33) and after prolonged exposure to this altitude (1.53±0.25; P<0.001). In conclusion, the acute exposure to hypobaric hypoxia induces aortic stiffening and reduction in subendocardial oxygen supply/demand index. Renin-angiotensin-aldosterone system does not seem to play any significant role in these hemodynamic changes. Clinical Trial Registration - URL: https://www.clinicaltrialsregister.eu/. Unique identifier: 2008-000540-14.

Aims Previous studies investigating the effect of hypoxia on left ventricle focused on its global function, an approach that may not detect a selective dysfunction of subendocardial layers that are most sensitive to an inadequate oxygen supply. In the HIGHCARE study, aimed at exploring the effects of high altitude hypoxia on multiple biological variables and their modulation by an angiotensin receptor blocker, we addressed the effects of hypobaric hypoxia on both systolic and diastolic left ventricular geometry and function, focusing on echocardiographic assessment of left ventricle twist to indirectly examine subendocardial left ventricular systolic function. Methods and results In 39 healthy subjects, physiological and echocardiographic variables, including left ventricular twist and a simplified torsion-To-shortening ratio (sTSR), were recorded at sea level, at 3400 m, and at 5400 m altitude (Mount Everest base camp). Both left ventricular twist and sTSR were greater at 5400 m than at sea level (12.68 vs. 9.68 and 0.285 vs. 0.202, P < 0.05 for both), were linearly related to the reduction in arterial oxygen partial pressure (P < 0.01 for both), and were associated with significant changes in LV dimensions and contractility. No effects of angiotensin receptor blockade were observed on these variables throughout the study. Conclusion Our study, for the first time, demonstrates an increase in left ventricular twist at high altitude in healthy subjects exposed to high altitude hypoxia, suggesting the occurrence of subendocardial systolic dysfunction in such condition.

Arrhythmogenic Cardiomyopathy is a complex clinical entity, sometimes difficult to diagnose. Three main different patterns of disease expression characterize clinically this hereditary heart muscle disease: the “classic” right ventricular form (ARVC), the “left dominant” subtype (LDAC), with primary left ventricular involvement, and the “biventricular” variant, defined by parallel involvement of both ventricles. We report on a case of a 51 years old man with a strong family history of juvenile sudden cardiac death of supposed ischaemic origin and personal history of ventricular arrhythmias and supposed myocarditis. We demonstrate how an accurate anamnesis plus correct interpretation of traditional non invasive tests followed by more sophisticate new non invasive tests such as cardiac magnetic resonance and genetic testing allowed to reach the correct diagnosis

OBJECTIVE: Blood pressure (BP) measuring devices may become inaccurate at high altitude due to low barometric pressure. Aim of this study was to assess the changes in the accuracy of different types of BP measuring devices between sea level and high altitude, taking auscultatory measurements with mercury sphygmomanometer as reference. DESIGN AND METHOD: In the frame of HIGHCARE-ALPS project, we obtained multiple BP measurements in 39 healthy, normotensive volunteers (age:36.4 ± 8.5y, M/F:21/18), using a mercury (MER, reference), an aneroid (ANE), and two validated oscillometric devices [one for home (OSC-HBP; AND UA-767PC) and one for ambulatory (OSC-ABP; AND TM2430)] BP monitoring, at sea level and during acute exposure to high altitude (4559m, 437-439 Torr). BP measurements with the different devices were performed sequentially on the same arm in random order, consistent under both study conditions. RESULTS: Mean systolic (S) and diastolic (D)BP were higher at high altitude than at sea level (MER: 117.6/80.3 vs. 110.9/74.1 mmHg, p < 0.001) The mean differences in SBP between MER (reference) and the other devices at baseline and high altitude were 1.7 ± 6.5/0.6 ± 7.1 (OSC-ABP), -3.1 ± 5.3*/-3.8 ± 6.3* (ANE) and -1.2 ± 7.0/-5.0 ± 6.7* (OSC-HBP) respectively. The corresponding differences for DBP were -3.9 ± 5.9*/-4.5 ± 6.5* (OSC-ABP), -2.2 ± 5.1*-5.3 ± 6.7* (ANE) and -4.8 ± 7.6*/-1.8 ± 7.1 (OSC-HBP), (mmHg, *p < 0.01 vs. MER). The over or underestimations of BP values by tested devices as compared with MER were consistent and similar at sea level and high altitude, except for a greater underestimation of SBP by OSC-HBP (p = 0.01), and of DBP by ANE (p = 0.03) at altitude, and for a greater underestimation of DBP by OSC-HBP (p = 0.02) at sea level. In spite of the statistical significance, the absolute changes in the size of error between sea level and high altitude never exceeded 4 mmHg. The distribution of mean between-device differences within the group was

Blood pressure increases during acute exposure to high altitude in healthy humans. However, little is known on altitude effects in hypertensive subjects or on the treatment efficacy in this condition. Objectives of High Altitude Cardiovascular Research (HIGHCARE)-Andes Lowlanders Study were to investigate the effects of acute high-altitude exposure on 24-hour ambulatory blood pressure in hypertensive subjects and to assess antihypertensive treatment efficacy in this setting. One hundred untreated subjects with mild hypertension (screening blood pressure, 144.1±9.8 mm Hg systolic, 92.0±7.5 mm Hg diastolic) were randomized to double-blind placebo or to telmisartan 80 mg+modified release nifedipine 30 mg combination. Twenty-four-hour ambulatory blood pressure monitoring was performed off-treatment, after 6 weeks of treatment at sea level, on treatment during acute exposure to high altitude (3260 m) and immediately after return to sea level. Eighty-nine patients completed the study (age, 56.4±17.6 years; 52 men/37 women; body mass index, 28.2±3.5 kg/m 2). Twenty-four-hour systolic blood pressure increased at high altitude in both groups (placebo, 11.0±9 mm Hg; P<0.001 and active treatment, 8.1±10.4 mm Hg; P<0.001). Active treatment reduced 24-hour systolic blood pressure both at sea level and at high altitude (147.9±11.1 versus 132.6±12.4 mm Hg for placebo versus treated; P<0.001; 95% confidence interval of the difference 10.9-19.9 mm Hg) and was well tolerated. Similar results were obtained for diastolic, for daytime blood pressure, and for nighttime blood pressure. Treatment was well tolerated in all conditions. Our study demonstrates that (1) 24-hour blood pressure increases significantly during acute high-altitude exposure in hypertensive subjects and (2) treatment with angiotensin receptor blocker-calcium channel blocker combination is effective and safe in this condition.

Background: Hypertension and severe obstructive sleep apnea (OSA)may independently contribute to left ventricular diastolic dysfunction. However, scanty data is available on this issue in hypertensives withmild.moderate OSA. Methods and results:Weperformed polysomnography, echocardiography and 24 h ambulatory blood pressure monitoring in 115 treated essential hypertensives with suspicion of OSA. After exclusion of severe/treated OSA and/or cardiovascular disease patients, mild.moderate OSA (5 ≥ apnoea/hypopnoea index b 30 events·h-1) was diagnosed in 47.3% of the remaining 91 patients, while 52.7% were free of OSA. Transmitral early (E) and late (A) peak flow velocities were assessed in 69 patients, and mitral annular velocity (E′) in 53. Compared to non- OSA, mild.moderate OSA heart rate was higher (p =0.031) while E/A was lower (p = 0.001) without differences in 24 h mean systolic and diastolic blood pressures (125.36 ± 12.46/76.46 ± 6.97 vs 128.63 ± 11.50/77.70 ± 7.72 mm Hg, respectively, NS). Patients with E′ > 10 cm/s and E/A > 0.8 showed a lower mean SpO2 than subjects with normal diastolic function (p = 0.004; p > 0.001). In a logistic regression model age, mean SpO2, daytime heart rate and nocturnal diastolic blood pressure fall were associated with altered relaxation pattern, independently from BMI and gender. Conclusions: In controlled hypertensives mild.moderate OSA may be associated with early diastolic dysfunction, independently from age, gender andmean blood pressure and in the absence of concentric left ventricular hypertrophy. Moreover nocturnal hypoxia may be a key factor in determining early diastolic dysfunction, under the synergic effects of hypertension and mild.moderate OSA.

Aim Many hypertensive subjects travel to high altitudes, but little is known on ambulatory blood pressure (ABP) changes and antihypertensive drugs' efficacy under acute and prolonged exposure to hypobaric hypoxia. In particular, the efficacy of angiotensin receptor blockers in this condition is unknown. This may be clinically relevant considering that renin-angiotensin system activity changes at altitude. The HIGHCARE-HIMALAYA study assessed changes in 24 h ABP under acute and prolonged exposure to increasing altitude and blood pressure-lowering efficacy and safety of an angiotensin receptor blockade in this setting. Methods and results Forty-seven healthy, normotensive lowlanders were randomized to telmisartan 80 mg or placebo in a double-blind, parallel group trial. Conventional and Ambulatory BPs were measured at baseline and on treatment: after 8 weeks at sea level, and under acute exposure to 3400 and 5400 m altitude, the latter upon arrival and after 12 days (Mt. Everest base camp). Blood samples were collected for plasma catecholamines, renin, angiotensin, and aldosterone. In both groups, exposure to increasing altitude was associated with: (i) significant progressive increases in conventional and 24 h blood pressure, persisting throughout the exposure to 5400 m; (ii) increased plasma noradrenaline and suppressed renin-angiotensin-aldosterone system. Telmisartan lowered 24 h ABP at the sea level and at 3400 m (between-group difference 4.0 mmHg, 95% CI: 2.2-9.5 mmHg), but not at 5400 m. Conclusion Ambulatory blood pressure increases progressively with increasing altitude, remaining elevated after 3 weeks. An angiotensin receptor blockade maintains blood pressure-lowering efficacy at 3400 m but not at 5400 m

The causes and development of lung fluid, as well as the integrity of the alveolar-capillary membrane at high altitude, are undefined. This study was conceived to see whether fluid accumulates within the lung with acute high altitude exposure, and whether this is associated with alveolar capillary membrane damage. We studied lung carbon monoxide diffusion (DLCO), its components – membrane diffusion (DM) and capillary volume (VC) and alveolar volume (VA) measured in 43 healthy subjects in Milan (122 m)and after 1 and 3 days at Capanna Regina Margherita (4559 m). DLCO measurement was adjusted for hemoglobin and inspired oxygen. We also measured plasma surfactant derived protein B (SPB) and Receptor of Advanced Glycation End-products (RAGE) as markers of alveolar-capillary membrane damage, and ultrasound lung comets as a marker of extravascular lung water. 21 subjects received acetazolamide and 22 placebo. DLCO was lower at Capanna Regina Margherita (day 1: 24.3 ± 4.7 and day 3: 23.6 ± 5.4 mL/mmHg/min), than in Milan (25.8 ± 5.5; p < 0.001 vs. day 1 and 3) due to DM reduction (Milan: 50.5 ± 14.6 mL/mmHg/min, Capanna Regina Margherita day 1: 45.1 ± 11.5 mL/mmHg/min, day 3: 43.2 ± 13.9 mL/mmHg/min; p < 0.05 Milan vs. day 3) with a partially compensatory VC increase (Milan: 96 ± 37 mL, Capanna Regina Margherita day 1: 152 ± 66 mL, day 3: 153 ± 59 mL; p < 0.001 Milan vs. day 1 and day 3). Acetazolamide did not prevent the fall in DLCO albeit, between day 1 and 3, such a trend was observed. Regardless of treatment lung comets increased from 0 to 7.2 ± 3.6 (p < 0.0001). SPB and RAGE were unchanged. Lung fluid increased at high altitude without evidence from plasma measurements, supporting alveolar-capillary damage

High-altitude exposure is characterized by the appearance of periodic breathing during sleep. Only limited evidence is available, however, on the presence of gender-related differences in this breathing pattern. In 37 healthy subjects, 23 male and 14 female, we performed nocturnal cardiorespiratory monitoring in the following conditions: (1) sea level; (2) first/ second night at an altitude of 3400 m; (3) first/second night at an altitude of 5400 m and after a 10 day sojourn at 5400 m. At sea level, a normal breathing pattern was observed in all subjects throughout the night. At 3400 m the apnea–hypopnea index was 40.3 33.0 in males (central apneas 77.6%, central hypopneas 22.4%) and 2.4 2.8 in females (central apneas 58.2%, central hypopneas 41.8%; P < 0.01). During the first recording at 5400 m, the apnea–hypopnea index was 87.5 35.7 in males (central apneas 60.0%, central hypopneas 40.0%) and 41.1 44.0 in females (central apneas 73.2%, central hypopneas 26.8%; P < 0.01), again with a higher frequency of central events in males as seen at lower altitude. Similar results were observed after 10 days. With increasing altitude, there was also a progressive reduction in respiratory cycle length during central apneas in males (26.9 3.4 s at 3400 mand 22.6 3.7 s at 5400 m). Females, who displayed a significant number of central apneas only at the highest reached altitude, were characterized by longer cycle length than males at similar altitude (30.1 5.8 s at 5400 m). In conclusion, at high altitude, nocturnal periodic breathing affects males more than females. Females started to present a significant number of central sleep apneas only at the highest reached altitude. After 10 days at 5400 m gender differences in the apnea–hypopnea index similar to those observed after acute exposure were still observed, accompanied by differences in respiratory cycle length.

AimsWe assessed the haemodynamic changes induced by exposure to high altitude hypoxia and the effects on them of acetazolamide, a drug prescribed to prevent and treat mountain sickness.Methods and resultsIn 42 subjects (21 males, age 36.8 ± 8.9 years) randomized to double blind acetazolamide 250 mg b.i.d. or placebo, pulse wave velocity and pulse wave parameters were assessed (PulsePen) at baseline; after 2-day treatment at sea level; within 6 h and on 3rd day of exposure to high altitude. Exposure to high altitude significantly increased diastolic (P < 0.005) and mean blood pressure (BP) (P < 0.05, after prolonged exposure) in placebo but not in the acetazolamide group. Therefore, subjects on acetazolamide showed significantly lower values of diastolic (P < 0.005) and mean BP (P < 0.05) at altitude. Furthermore, they also showed significantly lower values of systolic BP (P < 0.05). Pulse wave velocity did not change at high altitude, while the augmentation index, normalized for a theoretical heart rate of 75 b.p.m., significantly increased (P < 0.05) under placebo, but not under acetazolamide. In a multivariate model, unadjusted augmentation index at high altitude was not affected by BP changes, while significant determinants were heart rate and gender.ConclusionAcute exposure to high altitude induced a rise in brachial BP and changes in pulse waveform-derived parameters, independent from changes in mean BP and partly counteracted by treatment with acetazolamide. The impact of acetazolamide on the haemodynamic alterations induced by hypobaric hypoxia may be considered among the beneficial effects of this drug in subjects prone to mountain sickness.Clinical Trial Registration: EudraCT Number: 2010-019986-27

High-altitude tourism is increasingly frequent, involving also subjects with manifest or subclinical coronary artery disease. Little is known, however, on the effects of altitude exposure on factors affecting coronary perfusion. The aim of our study was to assess myocardial oxygen supply/demand ratio in healthy subjects during acute exposure at high altitude and to evaluate the effect of acetazolamide on this parameter. Forty-four subjects (21 men, age range: 24–59 years) were randomized to double-blind acetazolamide 250 mg bid or placebo. Subendocardial viability ratio and oxygen supply/demand ratio were estimated on carotid artery by means of a validated PulsePen tonometer, at sea level, before and after treatment, and after acute and more prolonged exposure to high altitude (4559 m). On arrival at high altitude, subendocardial viability ratio was reduced in both placebo (from 1.63±0.15 to 1.18±0.17; P<0.001) and acetazolamide (from 1.68±0.25 to 1.35±0.18; P<0.001) groups. Subendocardial viability ratio returned to sea level values (1.65±0.24) after 3 days at high altitude under acetazolamide but remained lower than at sea level under placebo (1.42±0.22; P<0.005 versus baseline). At high altitude, oxygen supply/demand ratio fell both under placebo (from 29.6±4.0 to 17.3±3.0; P<0.001) and acetazolamide (from 32.1±7.0 to 22.3±4.6; P<0.001), its values remaining always higher (P<0.001) on acetazolamide. Administration of acetazolamide may, thus, antagonize the reduction in subendocardial oxygen supply triggered by exposure to hypobaric hypoxia. Further studies involving also subjects with known or subclinical coronary artery disease are needed to confirm a protective action of acetazolamide on myocardial viability under high-altitude exposure.

Slow deep breathing improves blood oxygenation (SpO2) and affects hemodynamics in hypoxic patients. We investigated the ventilatory and hemodynamic effects of slow deep breathing in normal subjects at high altitude. We collected data in healthy lowlanders staying either at 4559 m for 2–3 days (Study A; N = 39) or at 5400 m for 12–16 days (Study B; N = 28). Study variables, including SpO2 and systemic and pulmonary arterial pressure, were assessed before, during and after 15 minutes of breathing at 6 breaths/min. At the end of slow breathing, an increase in SpO2 (Study A: from 80.267.7% to 89.568.2%; Study B: from 81.064.2% to 88.664.5; both p,0.001) and significant reductions in systemic and pulmonary arterial pressure occurred. This was associated with increased tidal volume and no changes in minute ventilation or pulmonary CO diffusion. Slow deep breathing improves ventilation efficiency for oxygen as shown by blood oxygenation increase, and it reduces systemic and pulmonary blood pressure at high altitude but does not change pulmonary gas diffusion.

Purpose: Low birth weight and accelerated postnatal growth appear to play a significant role in the pathogenesis of hypertensionandcardiovascular disease in adulthood.Theaimof the present studywas to characterize the factors determining pulse wave velocity (PWV) in teenagers and, in particular, to verify the relationship with birth weight, postnatal growth, timing of adiposity rebound, lifestyle, and hemodynamic parameters. Methods: Carotid-femoral and carotid-radial pulse wave velocities of 558 healthy teenagers (age range: 16.2–19.9 years) were determined by means of a PulsePen tonometer. Birth weight and gestational age were obtained from obstetrical records, and data regarding postnatal growth were obtained from pediatric clinical records. Results: No change in aortic PWV was found in association with birth weight, postnatal growth, and timing of adiposity rebound. However, the study showed a strong association between accelerated growth from 0 to 12 months and carotid-radialPWV(trend: p .02). Subjects with birth weight values 2,500 g showed higher values of upper limb PWV (p .05) and higher values of diastolic and mean arterial pressure (p .05). Stepwise regression analysis revealed that mean arterial pressure, age, and height were the main independent factors determining aortic PWV in this young population. Conclusions: These results suggest that there is no linear correlation between birth weight and hemodynamic parameters in teenagers; however, subjects characterized by very low birth weight and accelerated postnatal weight gain appear to demonstrate increased upper limb PWV and diastolic and mean arterial pressure values

The exposure of healthy subjects to high altitude represents a model to explore the pathophysiology of diseases related to tissue hypoxia and to evaluate pharmacological approaches potentially useful as a therapy for chronic diseases related to hypoxia. We explored the urinary peptidome to detect alterations induced by the exposure of subjects to different altitudes (sea level, high altitude = 3500 m, very high altitude = 5400 m) and to pharmacological treatment. Urine samples were collected from 47 subjects, randomly and blindly assigned to placebo (n = 24) or Telmisartan (n = 23). Samples were purified by the use of magnetic beads, then analysed by MALDI-TOF MS. Results showed that the urinary peptidome is not affected by the administration of Telmisartan, neither at the sea level nor at high and very high altitudes. In contrast, the urinary protein profiles are modified when subjects are exposed to high and very high altitudes, and we detected six peptides differentially expressed in hypobaric hypoxia at high or very high altitude compared to the sea level. Two of them were identified as fragments of the glycoprotein uromodulin and of the a1-antitrypsin. This is the first proteomic study showing that hypobaric hypoxia conditions affect the urinary peptidome.

Iron is tightly connected to oxygen homeostasis and erythropoiesis. Our aim was to better understand how hypoxia regulates iron acquisition for erythropoiesis in humans, a topic relevant to common hypoxia-related disorders. Fortyseven healthy volunteers participated in the HIGHCARE project. Blood samples were collected at sea level and after acute and chronic exposure to high altitude (3400-5400 m above sea level). We investigated the modifications in hematocrit, serum iron indices, erythropoietin, markers of erythropoietic activity, interleukin-6, and serum hepcidin. Hepcidin decreased within 40 hours after acute hypoxia exposure (P < .05) at 3400 m, reaching the lowest level at 5400 m (80% reduction). Erythropoietin significantly increased (P < .001) within 16 hours after hypoxia exposure followed by a marked erythropoietic response supported by the increased iron supply. Growth differentiation factor-15 progressively increased during the study period. Serum ferritin showed a very rapid decrease, suggesting the existence of hypoxia-dependent mechanism(s) regulating storage iron mobilization. The strong correlation between serum ferritin and hepcidin at each point during the study indicates that iron itself or the kinetics of iron use in response to hypoxia may signal hepcidin down-regulation. The combined and significant changes in other variables probably contribute to the suppression of hepcidin in this setting. © 2011 by The American Society of Hematology.

Background: high-altitude adaptation leads to progressive increase in arterial PaO2. In addition to increased ventilation, better arterial oxygenation may reflect improvements in lung gas exchange. Previous investigations reveal alterations at the alveolar-capillary barrier indicative of decreased resistance to gas exchange with prolonged hypoxia adaptation, but how quickly this occurs is unknown. Carbon monoxide lung diffusing capacity and its major determinants, hemoglobin, alveolar volume, pulmonary capillary blood volume, and alveolar-capillary membrane diffusion, have never been examined with early high-altitude adaptation. Methods and Results: lung diffusion was measured in 33 healthy lowlanders at sea level (Milan, Italy) and at Mount Everest South Base Camp (5,400 m) after a 9-day trek and 2-wk residence at 5,400 m. Measurements were adjusted for hemoglobin and inspired oxygen. Subjects with mountain sickness were excluded. After 2 wk at 5,400 m, hemoglobin oxygen saturation increased from 77.2 ± 6.0 to 85.3 ± 3.6%. Compared with sea level, there were increases in hemoglobin, lung diffusing capacity, membrane diffusion, and alveolar volume from 14.2 ± 1.2 to 17.2 ±1.8 g/dl (P < 0.01), from 23.6 ± 4.4 to 25.1 ± 5.3 ml·min-1·mmHg-1 (P < 0.0303), 63 ± 34 to 102 ± 65 ml·min-1·mmHg-1 (P < 0.01), and 5.6 ± 1.0 to 6.3 ± 1.1 liters (P < 0.01), respectively. Pulmonary capillary blood volume was unchanged. Membrane diffusion normalized for alveolar volume was 10.9 ± 5.2 at sea level rising to 16.0 ± 9.2 ml·min-1·mmHg -1·1-1 (P < 0.01) at 5,400 m. Conclusions: at high altitude, lung diffusing capacity improves with acclimatization due to increases of hemoglobin, alveolar volume, and membrane diffusion. Reduction in alveolar-capillary barrier resistance is possibly mediated by an increase of sympathetic tone and can develop in 3 wk. Copyright © 2011 the American Physiological Society.

Purpose: Acute mountain sickness (AMS) is a neurological disorder that may be unpredictably experienced by subjects ascending at a high altitude. The aim of the present study was to develop a predictive index, measured at an intermediate altitude, to predict the onset of AMS at a higher altitude. Methods: In the first part, 47 subjects were investigated and blood withdrawals were performed before ascent, at an intermediate altitude (3440 m), and after acute and chronic exposition to high altitude (Mount Everest Base Camp, 5400 m (MEBC1 and MEBC2)). Parameters independently associated to the Lake Louise scoring (LLS) system, including the self-reported and the clinical sections, and coefficients estimated from the model obtained through stepwise regression analysis were used to create a predictive index. The possibility of the index, measured after an overnight stay at intermediate altitude (Gnifetti hut, 3647 m), to predict AMS (defined as headache and LLS≥ 4) at final altitude (Capanna Margherita, 4559 m), was then investigated in a prospective study performed on 44 subjects in the Italian Alps. Results: During the expedition to MEBC, oxygen saturation, hematocrit, day of expedition, and maximum velocity of clot formation were selected as independently associated with LLS and were included in the predictive index. In the Italian Alps, subjects with a predictive index value≥ 5.92 at an intermediate altitude had an odds ratio of 8.1 (95% confidence limits = 1.7-38.6, sensitivity = 85%, specificity = 59%) for developing AMS within 48 h of reaching high altitude. Conclusion: In conclusion, a predictive index combining clinical and hematological parameters measured at an intermediate step on the way to the top may provide information on impending AMS. © 2011 by the American College of Sports Medicine.

Background: Little is known about the effects of cardiovascular drugs at high altitude. Objective: To assess 24-h blood pressure (BP) and heart rate (HR) during short-term altitude exposure in healthy normotensive persons treated with carvedilol or nebivolol. Methods: Participants were randomized in double-blind to placebo, nebivolol 5 mg once daily or carvedilol 25 mg b.i.d. Tests were performed at sea level (baseline and after 2 weeks treatment) and on second to third day at altitude (Monte Rosa, 4559 m), still on treatment. Data collection included conventional BP, 24-h ambulatory BP monitoring (ABPM), oxygen saturation (SpO2), Lake Louise Score and adverse symptoms score. Results: Twenty-four participants had complete data (36.4 ± 12.8 years, 14 men). Both beta-blockers reduced 24-h BP at sea level. At altitude 24-h BP increased in all groups, mainly due to increased night-time BP. Twenty-four-hour SBP at altitude was lower with carvedilol (116.4 ± 2.1 mmHg) than with placebo (125.8 ± 2.2 mmHg; P < 0.05) and intermediate with nebivolol (120.7 ± 2.1 mmHg; NS vs. others). Rate of nondipping increased at altitude and was lower with nebivolol than with placebo (33 vs. 71%; P = 0.065). Side effects score was higher with carvedilol than with placebo (P = 0.04), and intermediate with nebivolol. SpO2 at altitude was higher with placebo (86.1 ± 1.2%) than with nebivolol (81.7 ± 1.1%; P = 0.07) or carvedilol (81.1 ± 1.1%; P = 0.04). Conclusions: Both carvedilol and nebivolol partly counteract the increase in BP at altitude in healthy normotensive individuals but are associated with a lower SpO2. Carvedilol seems more potent in this regard, whereas nebivolol more effectively prevents the shift to a nondipping BP profile and is better tolerated. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Questo volume raccoglie i risultati di alcuni studi che ho condotto negli ultimi anni assieme al mio gruppo nel corso del Dottorato in “Ipertensione e Prevenzione del rischio cardiovascolare”. L’argomento che più abbiamo approfondito è stato il comportamento della pressione arteriosa durante esposizione di soggetti sani all’ipossia ipobarica d’alta quota. La medicina d’alta quota consente, come descritto nel capitolo 1 di questa tesi, di chiarire i meccanismi fisiopatologici alla base delle problematiche dei pazienti che spesso vediamo giornalmente nelle nostre Unità Coronariche o nei nostri ambulatori dello scompenso cardiaco o dell’ ipertensione. Portare un soggetto sano in alta quota permette, senza problemi dal punto di vista etico e senza interferenze da parte di comorbidità, di studiare l’effetto finale dell’ipossiemia sul sistema cardiovascolare e consente inoltre di studiare possibili interventi terapeutici. In questo contesto l’attività del nostro gruppo si è concentrata sullo studio della pressione arteriosa monitorata nelle 24 ore, del bilancio autonomico e, ultimamente, del comportamento delle proprietà elastiche delle arterie durante esposizione ad ipossia. Negli ultimi due anni, la mia attenzione nell’ambito dello studio dell’ipertensione arteriosa si è concentrata sull’utilizzo della valutazione della “stiffness” arteriosa mediante diverse metodiche (presentate nel capitolo 2) e sugli aspetti metodologici corretti che consentano di ottenere valori che siano realmente “affidabili”. La pressione arteriosa è per la maggior parte dei cardiologi un numero, spesso un valore approssimativamente misurato in modo più o meno accurato nell’ambito di una visita durante la quale l’interesse maggiore è andare alla ricerca di segni e sintomi di una cardiopatia organica. In questi anni ho imparato l’importanza di una corretta misurazione dei valori pressori; tutto quello che ho appreso e che cerco di trasmettere anche ai pazienti è riassunto nelle Linee G