Can Maternal Exercise Prevent High-Altitude Pulmonary Hypertension in Children?

Abstract

Leslie, Eric, Ann L. Gibson, Laura V. Gonzalez Bosc, Christine Mermier, Sean M. Wilson, and Michael R. Deyhle. Review: can maternal exercise prevent high-altitude pulmonary hypertension in children? High Alt Med Biol. 24:1–6, 2023.—Chronic high-altitude exposure reduces oxygen delivery to the fetus during pregnancy and causes pathologic pulmonary artery remodeling, This increases the risk of high-altitude pulmonary hypertension (PH), which is a particularly fatal disease that is difficult to treat. Therefore, finding ways to prevent high-altitude PH, including during the neonatal period, is preferable. Cardiorespiratory exercise can improve functional capacity and quality of life in patients with high-altitude PH. However, similar to other treatments and surgical procedures, the benefits are not enough to cure the disease after a diagnosis. Cardiorespiratory exercise by mothers during pregnancy (i.e., maternal exercise) has not been previously evaluated to prevent the development of high-altitude PH in children born and living at high altitude. This focused review describes the pathophysiology of high-altitude PH and the potential benefit of maternal exercise for preventing the disease caused by high-altitude pregnancies.

Introduction

High-altitude pulmonary hypertension (PH) is a specific type of Group III PH (caused by lung disease), as classified by the World Health Organization (Poor et al, 2012). High-altitude PH is characterized by abnormally high blood pressure in the pulmonary arteries (PAP) after chronic high-altitude (defined as ≥2,500 m) (Garrido et al, 2021) exposure, to which 81 million people around the world are regularly exposed (Tremblay and Ainslie, 2021). High-altitude PH is defined as a mean PAP ≥20 mmHg; however, a mean PAP ≥30 mmHg has also been used for high-altitude populations (Naeije, 2019).

High-altitude PH causes a thickening of the right ventricular wall in an attempt to overcome abnormally high PAP and to pump blood to the lungs effectively. This increases the risk of right ventricular hypertrophic cardiomyopathy, which reduces right ventricular cavity size and impairs myocardial electrical conduction. After compensatory mechanisms fail, cardiac output and exercise tolerance are impaired before right heart failure. Fetal and newborn development are especially influential periods that impact human health (Barker, 1995; Barker et al, 1990) and environmental stressors such as high-altitude hypoxia can alter development of several organs, including the brain, heart, and lungs (Ducsay et al, 2018).

Exercise throughout pregnancy, that is, maternal exercise, is an emerging field of research that has demonstrated positive effects for the newborn (Segabinazi et al, 2019; Vega et al, 2015). Maternal exercise in mice models lowers inflammation (a key mechanistic driver of high-altitude PH) following provocative challenges such as a lipopolysaccharide injection (Yamada et al, 2018) and a high-fat diet (Bae-Gartz et al, 2016). Therefore, pregnant women are a target population for exercise advocacy to prevent offspring disease and health complications.

Contrasting the known benefits of exercise against the pathogenetic mechanisms of newborn high-altitude PH, it is intriguing to consider that maternal exercise could counteract abnormal development caused by chronic high-altitude exposure. The purpose of this review is to evaluate the literature regarding the effect of maternal exercise on mechanisms driving high-altitude PH development. Specifically, this review summarizes the perinatal origins of high-altitude PH pathophysiology and potential exercise benefits to counteract mechanisms of high-altitude PH, and relays the available evidence of how maternal exercise may impact high-altitude PH development.

Perinatal Origins and Inflammatory Mediators of High-Altitude PH

Neonatal and childhood high-altitude PH are connected to a hypoxic intrauterine environment. Specifically, a delayed cardiopulmonary transition and inflammation-related pulmonary arterial remodeling characterize key hypoxic-mediated consequences on cardiopulmonary development. Lower cardiac outputs and impaired blood volume expansion have been reported in pregnant women at high altitude (Kametas et al, 2004). This hints at a lower placental circulation and, combined with already reduced partial pressure of oxygen (PO₂) at high altitude, lower maternal oxygen delivery to the fetus during pregnancy (i.e., gestational hypoxia).

Gestational high-altitude hypoxia is well known to increase the risk of pregnancy complications such as underdeveloped lungs (Ducsay et al, 2018) and low birth weights of the offspring (Herrera et al, 2010; Jean and Moore, 2012; Kametas et al, 2004; Lichty et al, 1957; Lorca et al, 2019; Moore, 2001; Niermeyer et al, 2009), although newborns in specific communities at high altitude have also been found with comparable birth weights to the average newborn birth weight within a state, such as in Leadville, Colorado, USA (Cotton et al, 1980).

Delayed cardiopulmonary transition

Gestational high-altitude hypoxia increases the risk of high-altitude PH by eliciting structural and functional changes in the fetal PAP (Leslie et al, 2021; Papamatheakis et al, 2013). In utero, the fetal PAP are naturally thicker (Penaloza and Arias-Stella, 2007) and the resulting higher vascular resistance in pulmonary circulation diverts blood away from the lungs through the foramen ovale and ductus arteriosus (Niermeyer, 2003; Rudolph, 1970). The high resistance is from fluid in the alveoli in utero and pulmonary vasoconstriction from low PO₂ in the pulmonary circulation (Rudolph, 1970).

Neonates at low altitude experience a sharp drop in PAP to nonhypertensive levels in the first few days after birth due to expansion of the lungs, pulmonary vasodilation from higher PO₂, a gradual receding of fluid, a thinning of pulmonary vascular smooth muscle (Rudolph, 1970), and a functional disuse preceding an anatomical closing of the foramen ovale and ductus arteriosus (Niermeyer, 2003).

However, high altitude causes a delay in cardiopulmonary transition and maintains higher pulmonary vascular resistance and elevated PAP into early childhood (Penaloza and Arias-Stella, 2007), promoting developmental consequences that can lead to right heart failure (Niermeyer, 2003). Moving to lower altitudes has promising effects in lowering mean PAP. For example, in a case study, a 15-year-old female had PAP drop from 44 to 17 mmHg after 11 months at low altitude (Grover et al, 1966). This has been repeated in a larger cohort with 11 young adult males (18–23 years of age), who relocated to low altitude for 2 years and their mean PAP lowered from 24 to 12 mmHg (Sime et al, 1971).

Perinatal hypoxia negatively impacts cardiopulmonary function by lowering pulmonary artery acceleration time, which is inversely proportional to PAP, as well as pulmonary valve peak flow velocity, and causing higher right ventricular hypertrophy and systolic pressure. These perinatal hypoxia-induced changes have been shown to persist in mice, despite living in normoxia from 3 to 8 weeks of age (Mundo et al, 2021). Therefore, questions remain as to whether there are long-lasting effects of gestational or perinatal hypoxia and if other recommendations other than low-altitude relocation are warranted.

Pulmonary artery inflammation

Beyond the factors that influence cardiopulmonary transition, a proinflammatory state caused by high-altitude exposure contributes to pulmonary artery remodeling and high-altitude PH. The inflammatory mediators involved tend to be related to the activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Several effects of hypoxia upregulate NF-κB signaling, including activation of hypoxia-inducible factors (HIF) (Wen et al, 2010), mitochondrial dysfunction (Chandel et al, 2000), endoplasmic reticulum stress (Leslie et al, 2021), and gastrointestinal permeability (Kannan et al, 2011; Ranchoux et al, 2017; Shellenberger et al, 2020). Cytokine transcription regulated by NF-κB also has a range of biological effects related to both inflammation and angiogenesis (Li et al, 2005; Maston et al, 2018; Maston et al, 2017; Mazzeo et al, 2001; Rastogi et al, 2012; Zell et al, 1997).

In addition, our recent metabolomic analysis (Leslie et al, 2021) showed broad increases in proinflammatory omega-6 fatty acid products (e.g., 15-keto PGE2 and linoleolglycerol) and reductions in anti-inflammatory oxylipins (e.g., the omega-3 fatty acid eicosapentaenoic acid and one of its metabolites, 5-hydroxyeicosapentaenoic acid) in fetal sheep PAP after gestational high-altitude hypoxia. This suggests that inflammation related to high-altitude PH may be the result of not only increased expression of proinflammatory molecules (e.g., TNF-α, IL-1β, IL-6, 15-keto PGE2, and linoleolglycerol) but also through reduced anti-inflammatory omega-3 fatty acid metabolism.

Mechanistic Connections Related to Cardiopulmonary Delay and Inflammation

A key mechanism of hypoxia-induced cardiopulmonary transition delay is driven by HIF-1α-mediated inhibition of mammalian target of rapamycin (mTOR)c1 (Mundo et al, 2021) and mTORc2 (Leontieva and Blagosklonny, 2012), which prevent nonproliferative branching and elongation of conducting airways and fluid removal from the lungs through epithelial Na⁺ channels (Land et al, 2014). Since downstream targets of mTOR are normalized after exposure to normoxia in mice postweaning (Mundo et al, 2021), this shows that hypoxia-induced suppression of mTOR signaling in the lungs has a distinct influence on the pulmonary vascular resistance and lung development during the cardiopulmonary transition and the onset of newborn gas exchange.

However, there is relatively little information regarding the influence of exercise at high altitude on mTOR signaling. The available evidence shows mTOR signaling is blunted in adult skeletal muscle after resistance exercise following acute normobaric hypoxic exposure (Etheridge et al, 2011) and after prolonged and exhaustive cardiorespiratory exercise following 3 weeks of chronic high-altitude exposure (Margolis et al, 2018). Whether these impacts on mTOR signaling and protein synthesis in skeletal muscle are also found in the lungs is yet to be determined.

Long-term cardiorespiratory exercise training is a well-known anti-inflammatory stimulus that generally reduces expression of proinflammatory cytokines (e.g., IL-6, TNF-α), increases expression of anti-inflammatory cytokines (e.g., IL-10, IL-1RA), and downregulates toll-like receptor signaling on circulating leukocytes (Gleeson et al, 2011). Furthermore, 16 weeks of moderate-intensity treadmill running in mice (60 min/day, five times/week) promotes a shift from an M1 (proinflammatory) to an M2 (anti-inflammatory) macrophage phenotype (Kawanishi et al, 2013).

Metabolomic studies further show that moderate- to high-intensity cardiorespiratory exercise training benefits both healthy and diseased populations. Lowered expression of proinflammatory oxylipins such as prostaglandins has been found in professional or Olympic-level triathletes over 145 days of training (García-Flores et al, 2018) and lower linoleic acid derivatives (DiHODEs and DiHOMEs) have been found in the plasma of obese adults after a 14-week cardiorespiratory training program on a treadmill or cycle ergometer with progressing volume (30–40 minutes sessions four times/week) and intensity (60%–70% maximal heart rate to 75% maximal heart rate) (Grapov et al, 2020).

Patients with PH have been shown to achieve similar weekly volumes of exercise as the general population, although at lower intensities (Grünig et al, 2012). Therefore, there are clear benefits to cardiorespiratory exercise for patients with PH, which may offer a protective effect against high-altitude PH development and progression. Unfortunately, moderate-intensity cardiorespiratory exercise does not improve PAP in humans (Grünig et al, 2012) or nitric oxide availability in mice (Zimmer et al, 2017) sufficiently to reverse the course of disease. Moreover, there is limited evidence regarding the effectiveness of exercise training for patients with high-altitude PH when compared to other types of PH. Therefore, preventing high-altitude PH development will have the best outcomes for children born or living at high altitude. Because high-altitude PH may occur in utero, this begs the question: can cardiorespiratory exercise throughout pregnancy (i.e., maternal exercise) prevent offspring high-altitude PH?

Can Maternal Cardiorespiratory Exercise Help Prevent High-Altitude PH in Offspring?

The general benefits of maternal exercise

Despite the perceived benefits of exercise for the mother and fetus, only ∼12.9%–37.8% of pregnant women in the United States meet the American College of Obstetrics and Gynecologists' recommended physical activity guidelines (Hesketh and Evenson, 2016). Part of the difference between recommendation and practice may be from lack of physician endorsement of exercise when counseling patients (Newton and May, 2017), something that the American College of Sports Medicine is working to address through their Exercise is Medicine initiatives (https://www.exerciseismedicine.org/wp-content/uploads/2021/04/EIM_Rx-for-Health_Pregnancy.pdf).

Moderate-intensity maternal exercise on most days of the week, while understudied and underpracticed (Newton and May, 2017), improves maternal and offspring health and does not cause adverse fetal or neonatal health outcomes during uncomplicated pregnancies (ACOG Committee Opinion Number 804, 2015). Specifically for pregnant women, maternal exercise lowers the risk of gestational diabetes mellitus (ACOG Committee Opinion Number 804, 2015) and gestational hypertension (ACOG Committee Opinion, Number 804, 2015; Genest et al, 2012). Both of these conditions compromise uterine blood flow (Ducsay et al, 2018) and increase the risk of fetuses becoming hypoxic.

Therefore, physical activity guidelines for healthy pregnant women are the same as for the general population; these include resistance exercise twice a week (Newton and May, 2017) and moderate-intensity cardiorespiratory exercise every day for a total of 150 minutes each week (ACOG Committee Opinion Number 804, 2015). A recent meta-analysis supports these guidelines by showing that studies where pregnant women performed 140 minutes per week of moderate-intensity cardiorespiratory or resistance exercise had a 25% reduced risk of gestational diabetes mellitus and gestational hypertension (Davenport et al, 2018). However, greater duration or intensity of exercise further reduces the risk of gestational hypertension (Marcoux et al, 1989). A summary of the acute responses and chronic benefits of exercise at low altitude by pregnant mothers, the fetus, and children is provided in Table 1.

Table 1.

Known Fetal Acute Responses and Long-Term Health Benefits to Maternal Exercise at Low Altitude

Fetal acute response	Low altitude
Heart rate
Oxygen consumption
Cardiac output
Umbilical artery pressure
Uterine artery pressure

Long-term health benefits	Low altitude
Fat mass
Leptin
Neurogenesis
Oxidative stress
Pulmonary valve defects
Aortic valve defects
Inflammation

Low altitude = <2,500 m; high altitude = >2,500 m. Up arrows indicate an increased response, and double-sided horizontal arrows indicate no significant change.

Maternal exercise at high altitude

Several voluntary wheel running studies with pregnant rodents also show promising results. Maternal exercise may attenuate several of the putative mechanistic triggers of high-altitude PH in offspring, including lower rates of gestational hypertension and placental disease (Falcao et al, 2010).

There is evidence that maternal exercise may offer some protection from high-altitude PH development by lowering inflammation that drives abnormal pulmonary artery development during the prenatal and neonatal stages (Ducsay et al, 2018; Leslie et al, 2021). Specifically, offspring of dams who were physically active throughout pregnancy are protected against proinflammatory stressors such as maternal obesity and lipopolysaccharide injection evidenced by lower levels of IL-6 (Bae-Gartz et al, 2016) and IL-1β (Yamada et al, 2018), respectively. This may highlight maternal exercise interferes with known inflammatory mediators of high-altitude PH, such as IL-6 trans-signaling (Maston et al, 2018).

Despite the potential benefits of maternal exercise during high-altitude pregnancy, it is possible that maternal exercise could exacerbate hypoxia-related effects on the fetus, which contribute to high-altitude PH development. One example is decreased blood flow to the fetus since high altitude reduces uterine (Zamudio et al, 1995) and myometrial artery blood flow (Lorca et al, 2019). This may have detrimental consequences to the fetus when combined with exercise since acute exercise diverts blood to the working muscle. While a graded exercise test for pregnant women at low altitude only showed significant increased resistance to blood flow in the right, but not left uterine artery measured 2 minutes post-test (Kennelly et al, 2002), a greater vasoconstricted state at high altitude may exaggerate these responses.

However, despite reduced uterine and umbilical blood flow and PO₂ in fetal sheep, fetal oxygen uptake and heart rates remain unchanged (Clapp, 1980), which may be attributed to an increase in O₂ extraction (Clapp, 1980; Lotgering et al, 1985). There was otherwise no effect on any of these variables during submaximal exercise (Clapp, 1980). A study with pregnant women also showed that acute maternal exercise at high altitude did not affect fetal heart rates and there were no significant differences in ventilation or plasma concentrations of glucose, lactate, and catecholamines (Artal et al, 1995), indicating fetuses tolerate high-altitude exercise well.

There are also considerations for cardiopulmonary transition and fetal growth and immune response to high-altitude exercise. Exercise throughout pregnancy in rats downregulates placental mTOR protein expression (Mangwiro et al, 2019), suggestive of nutrient redirection to the mother rather than the fetus. While this did not result in fetal growth restriction, it is interesting to speculate the potential responses at high altitude given HIF-mediated inhibition of mTOR within the lungs (Mundo et al, 2021). To our knowledge, connections between placental and lung expression of mTOR in response to cardiorespiratory- or resistance-based maternal exercise or hypoxic exposure have not been made.

Conclusions and Future Directions

The available evidence for maternal exercise is promising as a potential, nonpharmacological strategy to protect the fetus from proinflammatory mechanisms driving high-altitude PH and sequalae of this intractable disease. Exercise training interventions for pregnant mothers at high altitude have not been performed, and is an important area of research needed to determine safety and efficacy of maternal exercise to prevent offspring high-altitude PH development—animal studies could be used as a first step to answer these questions.

Footnotes

Authors' Contributions

All authors contributed to this work as defined by the International Committee of Medical Journal Editors. E.L. and M.R.D.: conceptualized the article; E.L.: literature review and wrote the article; M.R.D.: lead editor; and A.L.G., L.V.G.B., C.M., and S.M.W.: supporting editors. All authors approved of its final version.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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