Francisco C. Villafuerte

Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders.

The hypoxic conditions at high altitudes present a challenge for survival, causing pressure for adaptation. Interestingly, many high-altitude denizens (particularly in the Andes) are maladapted, with a condition known as chronic mountain sickness (CMS) or Monge disease. To decode the genetic basis of this disease, we sequenced and compared the whole genomes of 20 Andean subjects (10 with CMS and 10 without). We discovered 11 regions genome-wide with significant differences in haplotype frequencies consistent with selective sweeps. In these regions, two genes (an erythropoiesis regulator, SENP1, and an oncogene, ANP32D) had a higher transcriptional response to hypoxia in individuals with CMS relative to those without. We further found that downregulating the orthologs of these genes in flies dramatically enhanced survival rates under hypoxia, demonstrating that suppression of SENP1 and ANP32D plays an essential role in hypoxia tolerance. Our study provides an unbiased framework to identify and validate the genetic basis of adaptation to high altitudes and identifies potentially targetable mechanisms for CMS treatment.

Chronic Mountain Sickness and the Heart

Chronic Mountain Sickness (CMS) is an important high-altitude (HA) pathology in most mountainous regions of the world. Although its most characteristic sign is excessive erytrocytosis (EE), in the more severe stages of the disease, high-altitude pulmonary hypertension (HAPH), with remodeling of pulmonary arterioles and right ventricular enlargement is commonly found. The degree of ventricular hypertrophy depends on the vasoconstrictor pulmonary response, the intensity of vascular resistance and the level of altitude, and therefore on the degree of hypoxemia. This chapter briefly summarizes the existing data regarding the clinical and pathophysiological features of the cardiopulmonary system in CMS, with emphasis in findings from research in the Andes. The literature shows variability in cardiac output values in CMS, which might be related to the degree of EE. Recent findings have shown that cardiac output (l/min) is lower in CMS when compared with sea-level (SL) dwellers. Mean pulmonary acceleration time (ms) is significantly lower in CMS subjects than in SL and HA natives, and pulmonary vascular resistance index (Wood units) is higher in CMS and HA natives when compared with SL dwellers. Systemic blood pressure has similar values in CMS patients and healthy HA natives, but some differences arise in its control mechanisms. Although CMS individuals have a less effective vasoconstrictor reflex, their tolerance to orthostatic stress is similar to that of healthy HA natives which might be explained in terms of the larger blood volume present in CMS subjects. At present research is directed to design strategies on pharmacological intervention for CMS treatment. Recently, a clinical trial with acetazolamide, in patients with CMS has proven to be effective in increasing mean pulmonary acceleration time and decreasing pulmonary vascular resistance index, which might be indirectly due the reduction of hematocrit.

Exercise Pathophysiology in Patients With Chronic Mountain Sickness

BACKGROUND Chronic mountain sickness (CMS) is characterized by a combination of excessive erythrocytosis,severe hypoxemia, and pulmonary hypertension, all of which affect exercise capacity. METHODS Thirteen patients with CMS and 15 healthy highlander and 15 newcomer lowlander control subjects were investigated at an altitude of 4,350 m (Cerro de Pasco, Peru). All of them underwent measurements of diffusing capacity of lung for nitric oxide and carbon monoxide at rest, echocardiography for estimation of mean pulmonary arterial pressure and cardiac output at rest and at exercise, and an incremental cycle ergometer cardiopulmonary exercise test. RESULTS The patients with CMS, the healthy highlanders, and the newcomer lowlanders reached a similar maximal oxygen uptake at 32 1, 32 2, and 33 2 mL/min/kg, respectively, mean SE( P 5 .8), with ventilatory equivalents for C O 2 vs end-tidal P CO 2 , measured at the anaerobic threshold,of 0.9 0.1, 1.2 0.1, and 1.4 0.1 mm Hg, respectively ( P , .001); arterial oxygen content of 26 1, 21 2, and 16 1 mL/dL, respectively ( P , .001); diffusing capacity for carbon monoxide corrected for alveolar volume of 155% 4%, 150% 5%, and 120% 3% predicted, respectively( P , .001), with diffusing capacity for nitric oxide and carbon monoxide ratios of 4.7 0.1 at sea level decreased to 3.6 0.1, 3.7 0.1, and 3.9 0.1, respectively ( P , .05) and a maximal exercise mean pulmonary arterial pressure at 56 4, 42 3, and 31 2 mm Hg, respectively ( P , .001). CONCLUSIONS The aerobic exercise capacity of patients with CMS is preserved in spite of severe pulmonary hypertension and relative hypoventilation, probably by a combination of increased oxygen carrying capacity of the blood and lung diffusion, the latter being predominantly due to an increased capillary blood volume.

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. Clinical Trial Registration— URL: . Unique identifier: [NCT01830530][1]. # Novelty and Significance {#article-title-38} [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.

Decreased plasma soluble erythropoietin receptor in high-altitude excessive erythrocytosis and Chronic Mountain Sickness

Excessive erythrocytosis (EE) is the hallmark of chronic mountain sickness (CMS), a prevalent syndrome in high-altitude Andean populations. Although hypoxemia represents its underlying stimulus, why some individuals develop EE despite having altitude-normal blood erythropoietin (Epo) concentration is still unclear. A soluble form of the Epo receptor (sEpoR) has been identified in human blood and competes directly for Epo with its membrane counterpart (mEpoR). Thus, reduced levels of circulating sEpoR could lead to higher Epo availability and ultimately to EE. We characterized the relationship between Epo and sEpoR, with hematocrit and hemoglobin concentration in healthy highlanders and CMS patients at 4,340 m in Cerro de Pasco, Peru. Our results show that EE patients show decreased plasma sEpoR levels and can be subdivided into two subgroups of normal and high plasma Epo concentration for the altitude of residence, with hemoglobin concentration rising exponentially with an increasing Epo-to-sEpoR ratio (Epo/sEpoR). Also, we showed that the latter varies as an inverse exponential function of arterial pulse O2 saturation. Our findings suggests that EE is strongly associated with higher Epo/sEpoR values, leading to elevated plasma Epo availability to bind mEpoR, and thereby a stronger stimulus for augmented erythropoiesis. Differences in the altitude normal and high Epo CMS patients with a progressively higher Epo/sEpoR supports the hypothesis of the existence of two genetically different subgroups suffering from EE and possibly different degrees of adaptation to chronic high-altitude hypoxia.

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

New genetic and physiological factors for excessive erythrocytosis and Chronic Mountain Sickness

In the last few years, genetic and functional studies have provided important insight on the pathophysiology of excessive erythrocytosis (EE), the main sign of Chronic Mountain Sickness (CMS). The recent finding of the association of the CMS phenotype with a single-nucleotide polymorphism (SNP) in the Sentrin-specific Protease 1 (SENP1) gene, and its differential expression pattern in Andean highlanders with and without CMS, has triggered large interest in high-altitude studies because of the potential role of its gene product in the control of erythropoiesis. The SENP1 gene encodes for a protease that regulates the function of hypoxia-relevant transcription factors such as Hypoxia-Inducible Factor (HIF) and GATA, and thus might have an erythropoietic regulatory role in CMS through the modulation of the expression of erythropoietin (Epo) or Epo receptors. The different physiological patterns in the Epo-EpoR system found among Andeans, even among highlanders with CMS, together with their different degrees of erythropoietic response, might indicate specific underlying genetic backgrounds, which in turn might reflect different levels of adaptation to lifelong high-altitude hypoxia. This minireview discusses recent genetic findings potentially underlying EE and CMS, and their possible physiological mechanisms in Andean highlanders.

Blood pressure response to six-minute walk test in hypertensive subjects exposed to high altitude: effects of antihypertensive combination treatment

ABSTRACT Background Limited evidence exists on blood pressure (BP) responses to exercise in hypertensive subjects exposed to high altitude, and on the effects of antihypertensive treatment in this setting. We aimed to asses BP response to submaximal exercise in hypertensive lowlanders acutely exposed to high altitude, and the effects of a calcium antagonist–angiotensin receptor blocker combination in this condition. Methods 89 mild-hypertensive participants in HIGHCARE-ANDES study performed a six-minute walk test in 3 conditions: at sea-level off-treatment; at sea-level after 6weeks of double-blind treatment with telmisartan 80mg+slow release nifedipine 30mg or with placebo; on the first full day of permanence at 3260m altitude under randomized treatment. Results The distance walked in 6min was reduced by about 10% at high altitude in both groups (p Conclusions In mild hypertensives, acute exposure to high altitude enhances the BP response to exercise. Such an enhanced response is effectively reduced by telmisartan/nifedipine combination therapy, without affecting exercise performance.

Plasma soluble erythropoietin receptor is decreased during sleep in Andean highlanders with Chronic Mountain Sickness.

Andean highlanders suffering from Chronic Mountain Sickness (CMS) show consistently lower levels of plasma soluble erythropoietin (Epo) receptor (sEpoR) and higher Epo-to-EpoR ratios (Epo/sEpoR) during sleep compared with their healthy counterparts. This indicates higher blood Epo availability in CMS patients and continuous nocturnal erythropoietic stimulus. Additionally, morning Epo/sEpoR and mean sleep-time SpO2 are independent main predictors of Hct. These findings support the role of the Epo system in the development of excessive erythrocytosis in CMS.

High-Altitude Pulmonary Hypertension

Life at high altitude challenges the organism to cope with the environmental and physiological stress of hypoxia, the low ambient O2 partial pressure that results from the drop in barometric pressure as altitude increases. The physiology of high altitude residents responds to this situation in an attempt to maintain a normal cellular oxygenation through numerous mechanisms. Among these, the increase in hematocrit and hemoglobin concentration, and the elevation of pulmonary artery pressure (PAP) represent hallmark mechanisms in the response to high-altitude chronic hypoxia directed to increase blood O2 carrying capacity and redistribute blood to optimally ventilated lung areas, respectively. A large or excessive increase in hemoglobin concentration and/or in PAP, however, is associated with potentially fatal illnesses such as chronic mountain sickness (CMS), or Monge’s disease, and high-altitude pulmonary hypertension (HAPH). Rotta et al. were the first to describe hemodynamics in one CMS patient in the Peruvian Andes at 4,540 m. This patient showed a mean PAP of 35 mmHg, arterial blood oxygen saturation (SaO2) of 75%, and a hemoglobin concentration of 26 g/dL. Some years later, Penaloza et al. reported their hemodynamic observations in ten cases of CMS at 4,300 m. In these studies they found mean values of PAP of 47 ± 17.7 mmHg, SaO2 of 69.6 ± 4.9%, and hemoglobin concentration of 24.7 ± 2.4 g/dL. At that time, the authors described these patients as having a type of hypoxic cor pulmonale, in contrast to the hypertensive cor pulmonale observed in primary pulmonary hypertension or idiopathic pulmonary arterial hypertension. Historical terms used in different mountainous regions for this high-altitude disease, which has excessive elevation of PAP as a common characteristic, are CMS of vascular type, high-altitude heart disease, hypoxic cor pulmonale, infant subacute mountain sickness, pediatric high-altitude heart disease, and adult subacute mountain sickness.