Efficacy and tolerability of bevacizumab in patients with severe Covid-19.

On the basis of Covid-19-induced pulmonary pathological and vascular changes, we hypothesize that the anti-vascular endothelial growth factor (VEGF) drug bevacizumab might be beneficial for treating Covid-19 patients. From Feb 15 to April 5, 2020, we conducted a single-arm trial (NCT04275414) and recruited 26 patients from 2-centers (China and Italy) with severe Covid-19, with respiratory rate ≥30 times/min, oxygen saturation ≤93% with ambient air, or partial arterial oxygen pressure to fraction of inspiration O2 ratio (PaO2/FiO2) >100 mmHg and ≤300 mmHg, and diffuse pneumonia confirmed by chest imaging. Followed up for 28 days. Among these, bevacizumab plus standard care markedly improves the PaO2/FiO2 ratios at days 1 and 7. By day 28, 24 (92%) patients show improvement in oxygen-support status, 17 (65%) patients are discharged, and none show worsen oxygen-support status nor die. Significant reduction of lesion areas/ratios are shown in chest computed tomography (CT) or X-ray within 7 days. Of 14 patients with fever, body temperature normalizes within 72 h in 13 (93%) patients. Relative to comparable controls, bevacizumab shows clinical efficacy by improving oxygenation and shortening oxygen-support duration. Our findings suggest bevacizumab plus standard care is highly beneficial for patients with severe Covid-19. Randomized controlled trial is warranted.

Upward Shift and Steepening of the Blood Pressure Response to Exercise in Hypertensive Subjects at High Altitude.

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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01830530.

Renin-Angiotensin-Aldosterone System Is Not Involved in the Arterial Stiffening Induced by Acute and Prolonged Exposure to High Altitude.

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.

A brief period of intensive cardiac rehabilitation improves global longitudinal strain and diastolic function after a first uncomplicated myocardial infarction.

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 (KLV) from the deceleration time (DT), LVEF, systolic and diastolic volumes, wall motion score index (WMSI). At baseline, groups had similar GS%, KLV, LVEF, DT, E/e', systolic and diastolic volumes, WMSI. Rehabilitation increased peak VO2 by 18% (P < 0.05) and improved GS%, KLV, 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.

Clinical correlates of autonomic response during tilting test in hypertrophic cardiomyopathy.

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.

Effects of hypobaric hypoxia exposure at high altitude on left ventricular twist in healthy subjects: data from HIGHCARE study on Mount Everest.

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 (12.6° vs. 9.6° 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.

Ambulatory blood pressure in untreated and treated hypertensive patients at high altitude: the High Altitude Cardiovascular Research-Andes study.

UNLABELLED: 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. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01830530.

Diastolic dysfunction in controlled hypertensive patients with mild-moderate obstructive sleep apnea.

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 with mild-moderate OSA. METHODS AND RESULTS: We performed polysomnography, echocardiography and 24h 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<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 24h mean systolic and diastolic blood pressures (125.36 ± 12.46/76.46 ± 6.97 vs 128.63 ± 11.50/77.70 ± 7.72 mmHg, 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 and mean 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.

Changes in 24 h ambulatory blood pressure and effects of angiotensin II receptor blockade during acute and prolonged high-altitude exposure: a randomized clinical trial.

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.

Acute high-altitude exposure reduces lung diffusion: data from the HIGHCARE Alps project.

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.

Changes in subendocardial viability ratio with acute high-altitude exposure and protective role of acetazolamide.

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.

High-altitude hypoxia and periodic breathing during sleep: gender-related differences.

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 cardio-respiratory 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 m and 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.

Effects of acetazolamide on central blood pressure, peripheral blood pressure, and arterial distensibility at acute high altitude exposure.

AIMS: We 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 RESULTS: In 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. CONCLUSION: Acute 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.

Effects of slow deep breathing at high altitude on oxygen saturation, pulmonary and systemic hemodynamics.

Slow deep breathing improves blood oxygenation (Sp(O2)) 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 Sp(O2) 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 Sp(O2) (Study A: from 80.2±7.7% to 89.5±8.2%; Study B: from 81.0±4.2% to 88.6±4.5; 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.

Role of birth weight and postnatal growth on pulse wave velocity in teenagers.

PURPOSE: Low birth weight and accelerated postnatal growth appear to play a significant role in the pathogenesis of hypertension and cardiovascular disease in adulthood. The aim of the present study was 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-radial PWV (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.

Effects of beta-blockade on exercise performance at high altitude: a randomized, placebo-controlled trial comparing the efficacy of nebivolol versus carvedilol in healthy subjects.

AIMS: Exposure to high altitude (HA) hypoxia decreases exercise performance in healthy subjects. Although ß-blockers are known to affect exercise capacity in normoxia, no data are available comparing selective and nonselective ß-adrenergic blockade on exercise performance in healthy subjects acutely exposed to HA hypoxia. We compared the impact of nebivolol and carvedilol on exercise capacity in healthy subjects acutely exposed to HA hypobaric hypoxia. METHODS: In this double-blind, placebo-controlled trial, 27 healthy untrained sea-level (SL) residents (15 males, age 38.3 ± 12.8 years) were randomized to placebo (n = 9), carvedilol 25 mg b.i.d. (n = 9), or nebivolol 5 mg o.d. (n = 9). Primary endpoints were measures of exercise performance evaluated by cardiopulmonary exercise testing at sea level without treatment, and after at least 3 weeks of treatment, both at SL and shortly after arrival at HA (4559 m). RESULTS: HA hypoxia significantly decreased resting and peak oxygen saturation, peak workload, VO(2) , and heart rate (HR) (P < 0.01). Changes from SL (no treatment) differed among treatments: (1) peak VO(2) was better preserved with nebivolol (-22.5%) than with carvedilol (-37.6%) (P < 0.01); (2) peak HR decreased with carvedilol (-43.9 ± 11.9 beats/min) more than with nebivolol (-24.8 ± 13.6 beats/min) (P < 0.05); (3) peak minute ventilation (VE) decreased with carvedilol (-9.3%) and increased with nebivolol (+15.2%) (P= 0.053). Only peak VE changes independently predicted changes in peak VO(2) at multivariate analysis (R= 0.62, P < 0.01). CONCLUSIONS: Exercise performance is better preserved with nebivolol than with carvedilol under acute exposure to HA hypoxia in healthy subjects.

Modulation of urinary peptidome in humans exposed to high altitude hypoxia.

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 α1-antitrypsin. This is the first proteomic study showing that hypobaric hypoxia conditions affect the urinary peptidome.

High-altitude exposure of three weeks duration increases lung diffusing capacity in humans.

BACKGROUND: high-altitude adaptation leads to progressive increase in arterial Pa(O2). 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)·l(-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.