Surviving and thriving: impact of altitude on cardiac remodelling

This editorial refers to ‘Cardiac remodelling in the highest city in the world: effects of altitude and chronic mountain sickness’, by S. Doutreleau et al., https://doi.org/10.1093/eurjpc/zwac166. Chronic mountain sickness (CMS) is a public health concern in the Andean mountains and other mountainous regions of the world.1 The Andes occupies more than 2 500 000 km² and has a population of around 85 million (45% of the total country population).2 High altitude (HA) natives live in a state of hypobaric hypoxia with low ambient partial pressure of oxygen, which increases their risk of developing alveolar hypoxia, hypoxaemia, and polycythaemia. However, healthy HA natives can perform similar and often even more strenuous physical activities than people living at sea level.1 This phenomenon is due to adaptive mechanisms at the tissue level involving the oxygen transport system, decreasing the total pO2 gradient from ambient hypoxic air to mixed venous blood. Often during the fourth decade, when healthy HA natives undergo a decline in the ability to adapt to hypoxic conditions at HAs, they develop CMS and exhibit an accentuated form of hypoxaemia and exaggerated polycythaemia.2 The study of Doutreleau et al.3 is rich in data from the Expedition 5300 project, a scientific expedition investigating the effect of low oxygen levels on health. They present an interesting evaluation of cardiac remodelling and haemodynamic changes at rest and during exercise in healthy lowlanders (n = 18) and highlanders with (n = 38) and without CMS (n = 17) as assessed by the Qinghai score and echocardiography. They confirm that the increase in altitude is accompanied by right heart dilation and impairment in right ventricle (RV) systolic function along with left ventricle (LV) concentric remodelling with diastolic dysfunction and increase in relative wall thickness. These cardiac remodelling changes were largely seen in moderate-to-severe CMS patients, in addition to greater dilatation of both the RV end-diastolic area and the right atrial volume, which were significantly correlated with resting and exercise mean pulmonary artery pressure (mPAP) values. Arias-Stella and Saldana4 performed autopsies in Andean natives and reported greater muscularization of the distal pulmonary arterial branches and RV hypertrophy. Possibly, the increased PAP observed among Andes natives frequently persists through multiple, overlapping membership generations and the right cavities can sustain such an increased pressure load over a lifetime at HAs. Furthermore, Doutreleau et al.3 demonstrate that PAP was higher both at rest and during exercise in healthy highlanders at 5100 m which, together with total blood volume and SpO2 changes, are associated with right heart remodelling. They also report that moderate-to-severe CMS subjects had a higher pulmonary vascular resistance (PVR) at rest and a larger increase in PAP during exercise. It has previously been well described that overall mPAP is higher in patients during exercise and HA due to associated increases in cardiac output and pulmonary artery wedge pressure,5 and this has been again observed by Doutreleau et al.3. Haemodynamics, such as mPAP, were higher both at rest and during exercise in healthy highlanders at 5100 m compared with lowlanders and, to a major extent, moderate-to-severe CMS subjects had a significantly greater increase in mPAP during exercise. A distinct finding was reported by Groves et al.6 in an analysis of healthy Tibetans at 3658 m, who exhibited resting pulmonary arterial pressures in the normal sea-level range and minimal hypoxic pulmonary vasoconstriction at rest and during exercise. Another study also reported that PAP in Andeans living between 3700 and 4540 m is similar to that in healthy whites after acute exposure to a comparable altitude.2 It remains questionable whether these differences in PAP reflect genetic adaptation of Tibetans and Andeans to HAs. Haemodynamic studies such as Doutreleau et al.3 have not provided sufficient information on the ancestry of the Andean population studied. The role of genetic, epigenetic, and environmental factors responsible for cardiac remodelling and pulmonary haemodynamics that allow certain ethnic groups to better adapt to HA than other ethnic groups is still unknown. Therefore, there is a need for investigating such factors that may play a role in HA adaptation. The main strength of this study is the investigation of a complex and potentially challenging population whose life circumstances placed them in a vulnerable state of eventually developing CMS. The limitation is the inclusion of only middle-aged Andean Peruvian men, particularly of Quechua ancestry. In this regard, the study does not consider sex and ethnicity differences of altitude on cardiac remodelling. Studies have shown that there are ethnic differences among Tibetan, Andean, and Caucasian populations.5 In this sense, native Tibetans and Ethiopians are believed to be the most adapted ethnic groups compared with Andeans and Han immigrants.7 This adaptation is essentially reflected in lower Hb concentrations and therefore in a lower prevalence of excessive erythrocytosis (EE) and CMS. Accordingly, the lowest values are found in Tibetans from Qinghai, China, with a CMS prevalence of 1.21%, whereas in Han immigrants, it was 5.6% in the same city. In the Andes, the prevalence of CMS has been evaluated mainly in three locations: Puno and Cerro de Pasco in Perú and in La Paz, Bolivia. In Puno (3800 m), the prevalence was 6%, and in La Paz (3600 m), it was 5.2%.7 Doutreleau et al.3 included middle-aged men due to study site limitations in which subject recruitment was carried out only through the mining industry in La Rinconada, where mainly men work. Leon-Velarde et al.8 have shown that CMS prevalence within a particular population varies considerably across gender and age ranges. A higher prevalence is observed with advanced age, both in men and in women, and this increase is associated with age-related declines in ventilation, peak expiratory flow, and SaO2. In Cerro de Pasco, Perú, the prevalence of CMS among young adults (20–29 years) is around 7% but can reach 33% in older adults (>60 years).8 A higher prevalence is also observed in men than in women, and in post-menopausal women compared with pre-menopausal women.8,9 There are several explanations for this variation, but pre-menopausal women may present a protection against the development of EE due to an effect of female hormones on ventilation and by menstruation acting as regular natural phlebotomies. This may explain the important role of menopause, and particularly of progesterone, in the susceptibility to developing CMS.8 What are the age- and sex-associated changes in cardiac remodelling among Andean natives? The answer to this remains elusive, with a need for conducting future studies for obtaining longitudinal data on both men and women of varying race and ethnic backgrounds. Doutreleau et al.3 report that in La Rinconada (5100–5300 m), the exercise heart rate during the highest load is significantly lower than in Puno (3800 m), despite the same ‘relative’ level (i.e. same % of maximal HR). On the other hand, Bärtsch et al.2 report that for a given level of exercise, the heart rate is greater at altitude. This raises some very interesting questions about the formula used in the study to estimate the theoretical maximal heart rate, which has been determined from heart rate response in acute and not chronic hypoxia. This would have possibly resulted in the reporting of overestimated values since the studied CMS population corresponds to a chronic hypoxia state rather than acute hypoxia. Within the findings of Doutreleau et al.,3 important and novel observations are reported on one of the world’s most vulnerable populations living in the extreme regions of the Andes mountains, whose hypoxic environment directly impacts their health, functioning, and quality of life. There is a strong relationship between the increase in altitude with pulmonary haemodynamics and right/left cavities of the heart, contributing to the increase of mPAP at rest and during exercise, as well as both the hypertrophic effect and the dilation process in RV and concentric remodelling with diastolic dysfunction in LV. In particular, moderate-to-severe CMS patients, compared with those without CMS, were found to have the greatest dilatation of both the RV end-diastolic area and the RA volume along with a higher PVR at rest and a greater increase in mPAP during exercise. This raises an important question regarding the relationship between chronic exposure to hypoxic environments and the progression of heart failure or the development of HA pulmonary hypertension. Chronic mountain sickness is more commonly seen in individuals with a family history of the condition.10 With rapid advances in genomic technologies and genetics analyses, it is now more important than ever to investigate the genetic basis of adaptation or maladaptation to altitude. This accelerated rate of discovery using newer technologies will raise the possibility of new targeted drug therapies [e.g. PPAR (alpha), EDNRB, EPAS1, and EGLN1] for CMS.10 This is a scientific and public health challenge that requires transdisciplinary and synergistic collaborations to accelerate towards the prevention of CMS among the most vulnerable populations living in the mountainous regions of the world.1 None declared.