Author + information
- Sergio Caravita, MD,
- Andrea Faini, MSc, PhD,
- Grzegorz Bilo, MD, PhD,
- Francisco C. Villafuerte, MSc,
- Josè Luis Macarlupu, MSc,
- Morin Lang, MSc,
- Elisabetta Salvioni, MSc, PhD,
- Miriam Revera, MD, PhD,
- Andrea Giuliano, MD,
- Francesca Gregorini, BSc,
- Giuseppe Mancia, MD, PhD,
- Piergiuseppe Agostoni, MD, PhD and
- Gianfranco Parati, MD, PhD∗ ()
- ↵∗Department of Cardiovascular Neural and Metabolic Sciences, S. Luca Hospital, Istituto Auxologico Italiano & University of Milan-Bicocca, Piazzale Brescia 20, Milan 20149, Italy
Acute exposure to high altitude induces a blood pressure (BP) rise in healthy humans (1). Arterial hypertension is associated both with enhanced BP response to exercise and with increased sympathetic discharge in hypoxic conditions (2,3), which may increase the risk of adverse consequences in physically active patients who are exposed to high altitude; however, there is scant evidence available about BP in these conditions. We aimed to evaluate the BP response to exercise in hypertensive subjects acutely exposed to high altitude and to explore whether an antihypertensive drug treatment maintains its BP-lowering efficacy in this setting.
In the HIGHCARE-ANDES (HIGH altitude CArdiovascular REsearch in the ANDES) study (4), 55 mildly hypertensive subjects (age 57 ± 8 years; 26 females; body mass index 28.0 ± 14.5 kg/m2), who were randomized to double-blind placebo or to a fixed-dose antihypertensive combination treatment based on an angiotensin-receptor blocker (telmisartan 80 mg) and a calcium-channel blocker (nifedipine gastrointestinal therapeutic system [GITS] 30 mg), performed a step-incremental cardiopulmonary exercise test (CPET) on a cycle-ergometer both at sea level after 6 weeks of randomized treatment with placebo or telmisartan/nifedipine-GITS, and on the second day of stay at 3,260 m altitude (Huancayo, Peru). Arm BP was measured noninvasively at rest, during the last minute of each workload step, and at peak exercise, always with the same device (auscultatory method) and always by the same operator blinded to the individual’s treatment allocation. The ethics committees of Istituto Auxologico Italiano and Universidad Peruana Cayetano Heredia approved the study, which was conducted in accordance with the Declaration of Helsinki. All subjects gave written informed consent to participate, and the study was registered in the ClinicalTrials.gov database (NCT01830530). All statistical analyses have been performed using linear mixed-effects models with contrasts a posteriori accounting for repeated measurements. The false discovery rate has been used for multiple post-hoc comparisons.
CPET interruption occurred because of an excessive BP elevation 14 of 16 times and was more frequent in the placebo than in the actively treated group (10 times vs. 4 times) and at high altitude than at sea level (10 times vs. 4 times). Suspected exercise-induced myocardial ischemia (electrocardiogram changes or symptomatic angina) was the reason for interrupting CPET in 2 patients (1 in each treatment group) at high altitude. Going from sea level to high altitude, peak oxygen consumption and workload decreased by 12% and 14%, respectively (from 25.2 ± 5.0 ml/kg/min to 22.1 ± 3.4 ml/kg/min and from 130 ± 39 W to 111 ± 30 W; p < 0.001), without treatment-related differences, likely paralleling the known cardiac output decline at high altitude (5). However, the ventilatory equivalents for oxygen and carbon dioxide increased at each exercise step (p < 0.001), indicating chemoreflex activation. At each exercise step up to 120 W, systolic BP was higher at altitude compared with sea level, whereas diastolic BP at altitude was higher only at rest (Figure 1). At peak exercise, BP values did not show any statistically significant difference between high altitude and sea level. However, given that at altitude maximal exercise capacity was significantly reduced as compared with sea level, when BP was expressed as a function of individuals’ peak oxygen consumption (as a surrogate measure of cardiac output), the pressor response to peak exercise was significantly greater at high altitude than at sea level (p < 0.001).
Telmisartan/nifedipine-GITS effectively reduced BP at rest and throughout the exercise test both at sea level and at altitude, as compared with placebo (Figure 1).
In conclusion, mildly hypertensive subjects display a hypoxia-driven enhanced BP response to exercise during acute exposure to high altitude, which may carry some safety concerns, given the increasing number of individuals being exposed to high altitude either for leisure or work worldwide. The combination of a long-acting calcium-channel blocker and a long-acting angiotensin-receptor blocker turned out to be safe and effective in reducing such an enhanced BP response to exercise under hypobaric hypoxic conditions, without adversely affecting exercise capacity.
The authors thank Gian Piero Babbi and Stefano Ariotti (TaoMed) for the technical support given to this study, and Juan Eugenio Ochoa, MD, for the graphic help in figure preparation.
Please note: The HIGHCARE-ANDES project was supported by an unrestricted grant from Bayer Healthcare. Dr. Bilo has received speakers fees from Bayer Healthcare. Dr. Mancia has received speakers fees, consultation fees, or research grants from Boehringer Ingelheim, CVRx, Daiichi-Sankyo, Medtronic Vascular Inc., Menarini International, Merck Serono, Novartis, Pfizer, Recordati, Servier, Siron, and Takeda. Dr. Agostoni has served as a consultant for Menarini International and Bayer Healthcare; and has received speakers fees from Novartis, Daiichi-Sankyo, and Servier. Dr. Parati has received speakers or consultation fees from Bayer Healthcare, Daiichi-Sankyo, Menarini, CVRx, Pfizer, and Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Caravita and Faini contributed equally to this work.
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