Francesca Gregorini

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

AIMnMany 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.nnnMETHODS AND RESULTSnForty-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.nnnCONCLUSIONnAmbulatory 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.

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

AIMSnWe 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.nnnMETHODS AND RESULTSnIn 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.nnnCONCLUSIONnAcute 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.nnnCLINICAL TRIAL REGISTRATIONnEudraCT Number: 2010-019986-27.

Continuous positive airway pressure increases haemoglobin O2 saturation after acute but not prolonged altitude exposure

AIMSnIt is unknown whether subclinical high-altitude pulmonary oedema reduces spontaneously after prolonged altitude exposure. Continuous positive airway pressure (CPAP) removes extravascular lung fluids and improves haemoglobin oxygen saturation in acute cardiogenic oedema. We evaluated the presence of pulmonary extravascular fluid increase by assessing CPAP effects on haemoglobin oxygen saturation under acute and prolonged altitude exposure.nnnMETHODS AND RESULTSnWe applied 7 cm H(2)O CPAP for 30 min to healthy individuals after acute (Capanna Margherita, CM, 4559 m, 2 days permanence, and <36 h hike) and prolonged altitude exposure (Mount Everest South Base Camp, MEBC, 5350 m, 10 days permanence, and 9 days hike). At CM, CPAP reduced heart rate and systolic pulmonary artery pressure while haemoglobin oxygen saturation increased from 80% (median), 78-81 (first to third quartiles), to 91%, 84-97 (P < 0.001). After 10 days at MEBC, haemoglobin oxygen saturation spontaneously increased from 77% (74-82) to 86% (82-89) (P < 0.001) while heart rate (from 79, 64-92, to 70, 54-81; P < 0.001) and respiratory rate (from 15, 13-17, to 13, 13-15; P < 0.001) decreased. Under such conditions, these parameters were not influenced by CPAP.nnnCONCLUSIONnAfter ascent excessive lung fluids accumulate affecting haemoglobin oxygen saturation and, in these circumstances, CPAP is effective. Acclimatization implies spontaneous haemoglobin oxygen saturation increase and, after prolonged altitude exposure, CPAP is not associated with HbO(2)-sat increase suggesting a reduction in alveolar fluids.

Ambulatory Blood Pressure in Untreated and Treated Hypertensive Patients at High Altitude: The High Altitude Cardiovascular Research–Andes Study

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/m2). 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.nnClinical Trial Registration— URL: . Unique identifier: [NCT01830530][1].nn# Novelty and Significance {#article-title-38}nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01830530&atom=%2Fhypertensionaha%2F65%2F6%2F1266.atomBlood 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/m2). 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.

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.

AIMSnExposure to high altitude (HA) hypoxia decreases exercise performance in healthy subjects. Although β-blockers are known to affect exercise capacity in normoxia, no data are available comparing selective and nonselective β-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.nnnMETHODSnIn 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).nnnRESULTSnHA 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).nnnCONCLUSIONSnExercise performance is better preserved with nebivolol than with carvedilol under acute exposure to HA hypoxia in healthy subjects.

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.

Sex and acetazolamide effects on chemoreflex and periodic breathing during sleep at altitude.

OBJECTIVEnNocturnal periodic breathing occurs more frequently in men than in women with various clinical and pathophysiologic conditions. The mechanisms accounting for this sex-related difference are not completely understood. Acetazolamide effectively counteracts nocturnal periodic breathing, but it has been investigated almost exclusively in men. Our aim was to explore possible determinants of nocturnal periodic breathing in a high-altitude setting both in men and in women. We hypothesized that increased hypoxic chemosensitivity in men could be associated with the development of nocturnal periodic breathing at altitude more frequently than in women, and that acetazolamide, by leftward shifting the CO2 ventilatory response, could improve nocturnal periodic breathing at altitude in a sex-independent manner.nnnMETHODSnForty-four healthy lowlanders (21 women), randomized to acetazolamide or placebo, underwent cardiorespiratory sleep studies at sea level off treatment and under treatment on the first night after arrival at a 4,559-m altitude. Hypoxic and hypercapnic chemosensitivities were assessed at sea level.nnnRESULTSnMen, more frequently than women, exhibited increased hypoxic chemosensitivity and displayed nocturnal periodic breathing at altitude. Acetazolamide leftward shifted the CO2 set point and, at altitude, improved oxygenation and reduced periodic breathing in both sexes, but to a larger extent in men. Hypoxic chemosensitivity directly correlated with the number of apneas/hypopneas at altitude in the placebo group but not in the acetazolamide group.nnnCONCLUSIONSnThe greater severity of periodic breathing during sleep displayed by men at altitude could be attributed to their increased hypoxic chemosensitivity. Acetazolamide counteracted the occurrence of periodic breathing at altitude in both sexes, modifying the apneic threshold and improving oxygenation.nnnTRIAL REGISTRYnEU Clinical Trials Register, EudraCT; No.: 2010-019986-27; URL: https://www.clinicaltrialsregister.eu.

Ischemic changes in exercise ECG in a hypertensive subject acutely exposed to high altitude. Possible role of a high-altitude induced imbalance in myocardial oxygen supply-demand

a Dept of Cardiovascular, Neural and Metabolic Sciences, S. Luca Hospital, IRCCS Istituto Auxologico Italiano, Milan, Italy b Dept of Health Sciences, University of Milano-Bicocca, Milan, Italy c Laboratorio de Fisiologia Comparada, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Peru d Centro Cardiologico Monzino, IRCCS, Milan, Italy e Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy f Division of Pulmonary and Critical Care and Medicine, Department of Medicine, University of Washington, Seattle, WA, United States

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

AIMSnPrevious 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.nnnMETHODS AND RESULTSnIn 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.nnnCONCLUSIONnOur 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.