High altitude is generally defined as elevations greater than 2,500 m above sea level. Almost 140 million people worldwide live at high altitude, and a growing number of population ascend to high altitude for work or leisure. The Qinghai-Tibetan plateau in China occupies an area of nearly 2.5 million km2, with an average elevation exceeding 4,500 m. As of 2015, the National Tibetan Plateau Data Center of China reported that the resident population in the Qinghai and Tibet provinces was over 9 million, and a great number of Han lowlanders permanently migrated to the plateau. However, increases in altitude are always accompanied by progressive reductions in partial oxygen pressure, barometric pressure, air temperature, and air humidity. A series of physiological adaptation in response to high-altitude exposure helps to maintain adequate tissue oxygen supply in humans. Acclimatizing to extreme environments at high altitudes brings great challenges for the cardiovascular system, especially in patients with preexisting cardiovascular conditions. There are great differences in cardiac physiological adaption to high altitudes between lowlanders after short-term exposure and lifelong inhabitants, whether at rest or during exercise. Lowlanders are generally thought to be unable to adapt to hypoxia well, and highlanders are known to have extraordinary exercise capacities at high altitudes. Recently, increasing evidence and advances have emerged in high-altitude medicine. Although numerous studies have described cardiac performance at high altitude, controversies still remain. This article includes recent data on hypoxia-induced changes in cardiac function and structure. We reviewed the physiology and pathophysiology of the heart in lowlanders and acclimatized inhabitants at high altitude. Furthermore, we discussed the tolerance of patients with cardiovascular diseases at high altitude.
2. Pulmonary circulation at high altitude
Hypoxia at high altitude induces pulmonary vasoconstriction, resulting in increases in pulmonary vascular resistance (PVR) and pulmonary arterial pressure, which are usually moderate. Motley et al first described hypoxic pulmonary vasoconstriction assessed in 5 subjects by right heart catheterization with 10% inspired oxygen, and found that mean pulmonary artery pressure (PAP) increased from 13 to 23 mmHg. Studies have demonstrated that high-altitude-induced increases in pulmonary arterial pressure are generally associated with the absolute altitude attained and duration exposed to high altitude.[7,8] Our previous study included 91 healthy lowlanders ascending to 3,700 m within 24 h and staying there for 1 year. This study reported that the mean PAP was higher after acute exposure than chronic acclimatization to high altitude. For lifelong highlanders, Huez et al observed that mean PAPs were higher in healthy Aymara people than lowlanders at sea level, but they were lower than those in lowlanders after acute high-altitude exposure, suggesting an acclimatization mechanism of pulmonary vessels adapted to chronic hypoxia. The increase of PVR is observed both in lowlanders and native highlanders at high altitude. Additionally, exercise at high altitude is usually accompanied with a pronounced increase in PAP, both after acute exposure and during chronic acclimatization.[12,13] Banchero et al reported that mean PAP increased by nearly 100% during exercise in high-altitude lifetime residents.
Hypoxic pulmonary vasoconstriction is a unique homeostatic mechanism of pulmonary circulation that maintains the optimal balance of ventilation and perfusion, although it also contributes to hypoxic pulmonary hypertension (PH) at high altitudes. Previous study has observed that hypoxia-induced pulmonary vasoconstriction strengthened during the first 1–2 h of high-altitude exposure. Hypoxic pulmonary vasoconstriction is intrinsic to the smooth muscle cells of pulmonary arteries and is secondarily modulated by an endothelial mechanism. Whether hypobaric exposure is involved in the development of pulmonary vasoconstriction is poorly understood. To our knowledge, Boos et al observed higher right ventricular (RV) systolic pressure in hypobaric hypoxia compared to that in normobaric hypoxia after exercise but not at rest, indicating that hypobaric exposure itself might contribute to pulmonary vasoconstriction at least after exercise. The inhibition of voltage-gated potassium channels localized in smooth muscle cells induces initial hypoxic vasoconstriction and explains the immediate response. PVR increased rapidly in 5 min of hypoxic exposure, tended to be stabilized after 2 h, and reached a maximal response after approximately 24 h. It was remarkable that oxygenation supplementation after 6 h of hypoxic exposure immediately reduced PVR, but could not reverse it to normal levels after 24 to 48 h of exposure to hypoxia. Hypoxic exposure was found to induce structural vessel remodeling, which almost occurs within the first 24 h. However, lifelong adaptation at high altitude exhibited a suppression of hypoxic pulmonary vasoconstriction. Penaloza and Arias-Stella pointed out that increased amounts of smooth muscle cells in the distal pulmonary arteries and arterioles should be mainly responsible for PH in healthy native highlanders. Furthermore, hypervolemia, polycythemia, and increased blood viscosity are considered secondary factors responsible for the increase in PAP.
Humans display genetic variation in pulmonary vasoconstriction at high altitude, and limited studies to date have validated the genetics of high-altitude-induced PH. Native Tibetans exhibit a lower incidence of PH than Ecuadorians and Bolivians living at comparable altitudes. Simonson et al demonstrated that positively selected haplotypes of EGLN1 and PPARA were involved in the high-altitude adaptation of Tibetans. Additionally, recent studies reported that the development of high-altitude PH may be associated with genetic polymorphisms of the HIF-2α gene among the Chinese Han population, and in ACE I/D genotypes among Kyrgyz highlanders.[23,24] According to the European Society of Cardiology guidelines, high-altitude-induced PH is classified as the third type of PH. In a previous study, we defined high-altitude-induced borderline PH as a mean PAP of 20 to 25 mmHg. Our previous study reported an incidence of high-altitude-induced borderline PH of 29% after acute 24-hour exposure, and 37% after 1-year exposure in lowlanders. Furthermore, that study identified the relationship between high-altitude-induced borderline PH and decreased cardiorespiratory fitness, suggesting that hypoxic PH possibly contributed to altitude-related limitations in exercise.
Rapid ascension to high altitude without appropriate acclimation to hypoxia possibly induces high-altitude pulmonary edema (HAPE), which is an important and preventable cause of death at high altitudes.[5,26] Exaggerated and heterogeneous hypoxic pulmonary vasoconstriction is recognized as the crucial pathophysiology of HAPE. In numerous clinical observations of patients with HAPE, remarkable increments in PAP after high-altitude exposure were revealed. HAPE pathology is characterized by dynamic changes in the permeability of the alveolar-capillary barrier and mechanical injurious damage. In general, HAPE occurrence depends on the absolute altitude attained, rate of ascent, intensity of exercise, and genetic susceptibility. Researchers have reported that HAPE incidence was less than 0.2% in general trekkers climbing to altitudes of 4,000–5,000 m over 3 d. The incidence of HAPE rose to 7% when ascending to the same altitudes within 1 d. However, in populations with previous history of HAPE, the likelihood of developing HAPE was 60% when ascending to the same altitude within 1–2 d.
Potential pharmacological agents to prevent hypoxic PH and HAPE mostly aim to inhibit hypoxic pulmonary vasoconstriction. NO is a key biologically active mediator regulating blood distribution to maintain normal ventilation-perfusion ratios. Hypoxia-induced PAP was found to be inversely related to exhaled NO levels. PAP was reported to be 3 times higher in patients with HAPE than in healthy subjects, and it could be decreased by NO inhalation. A 5-phosphodiesterase inhibitor could prevent cGMP degradation to maintain the bioavailability of NO in pulmonary artery smooth muscle cells. Ghofrani et al demonstrated that 5-phosphodiesterase inhibitor (sildenafil, 50 mg) intake reduced PAP elevations and further improved maximal exercise capacity at the Mount Everest base camp, at around 5,200 m altitude. However, endothelin receptor antagonists can block the vasoconstrictor effect of endothelin-1 to inhibit the hypoxia-induced contraction of pulmonary artery smooth muscles. Studies have reported that the endothelin receptor antagonist bosentan attenuated PAP in healthy subjects and individuals with a HAPE medical history.[33,34] Furthermore, several studies demonstrated that nifedipine or dexamethasone reduced PAP and could prevent HAPE occurrence.[35,36] Our previous study identified that dexamethasone could improve arterial oxygenation at high altitudes, suggesting its additional effects for acclimatization at high altitudes. Intriguingly, acetazolamide was a promising medicine for high-altitude PH, and also succeeded in the prevention and treatment of acute mountain sickness. To date, only nifedipine, tadalafil, and dexamethasone have been recommended for preventing HAPE in susceptible individuals. Thus, larger-scale controlled studies are needed to further evaluate the efficacy of these medicines for reducing hypoxia-induced elevated PAP and preventing HAPE, especially in susceptible individuals.
3. Left ventricular (LV) function at high altitude
Many studies have investigated cardiac physiology and pathology at high altitudes. Balasubramanian et al first reported increased rather than decreased LV systolic function, assessed by systolic time intervals using M-mode echocardiography. Similarly, another study (Operation Everest II) in the simulated altitude of 7,620 m observed a somewhat enhanced LV ejection fraction but decreased LV volumes. The decline of LV volumes was attributed to hypovolemia. Indeed, plasma volume decreased by almost 20% within the first few days of ascending to altitudes of 3,800 to 4,500 m and remained low level during chronic hypoxia.[42,43] Moreover, our previous study observed an increase in LV ejection fraction in healthy non-Tibetans after ascending to 3,700 m within 24 h, which was maintained high level after a few days, based on 2-dimensional echocardiography. With the advent of the novel speckle-tracking echocardiography technique, Osculati et al reported an increase in LV twist at high altitudes in healthy subjects, which can reveal the function of subendocardial fibers. As for native highlanders, studies showed that they had preserved LV systolic function when adapting to lifetime hypoxia, as lowlanders did.
Of note, previous studies identified that cardiac output increased along with tachycardia during initial exposure to high altitude, but it returned to normal levels accompanied by lower stroke volume (SV) after a few days of acclimatization. Our previous study also observed pronounced increases in cardiac output index within 24 h of exposure to 3,700 m, which subsequently decreased after 7 d of acclimatization. The fall in SV after high altitude exposure is evident throughout acclimatization, but its underlying mechanisms remain incompletely understood. Increased RV afterload, decreased plasma volume, increased sympathetic activity, and impaired relaxation have been recognized to contribute to SV reductions. The well-preserved LV systolic function indicates an excellent tolerance of the myocardium to extreme hypoxia environments. However, the effect of high altitude on ventricular diastolic function has not yet been clarified.
High attitude undoubtedly induces an altered diastolic filling pattern through decreased mitral flow E/A ratio, and prolonged isovolumic relaxation time in lowlanders and native highlanders.[10,48,49] The decreased transvalvular flow peak E-wave velocity and increased peak A wave velocity were recognized as decreased LV early filling and increased left atrial contraction. Recently, Maufrais et al proposed a new perspective, whereby intrinsic LV relaxation was not altered, according to an unchanged LV longitude strain rate during early diastole in the first week ascending to 4,350 m. This study also observed delayed LV untwisting but higher untwisting rate, which was the first mechanical component during diastole and contribute to early filling by creating an intraventricular pressure gradient. They considered that higher untwisting rate resulted from increased twisting under hypoxia, and delayed untwisting could attribute to lower preload. Additionally, isovolumic relaxation times at high altitudes tend to be prolonged, suggesting a slowed early diastolic relaxation. LV filling pressures after acute high-altitude exposure were generally considered to decrease, as assessed by E/eʼ (transmitral flow velocity to mitral annular tissue velocity during early diastole, using Doppler echocardiography), which could be explained by hypoxia-induced hypovolemia and increased sympathetic hyperactivity.[5,54] Additionally, studies reported a more delayed diastolic longitude strain and lower untwisting during early diastole in Sherpa people compared with lowlanders at high altitudes. This might imply a conversion from acute response to a lower LV filling pressure and greater systolic apical rotation to myocardial remodeling under chronic hypoxia over time.
Atrial contraction was previously considered to be enhanced to overcome impaired ventricular filling, as assessed by peak A wave velocity using Doppler echocardiography. However, our recent study using speckle-tracking echocardiography found that left atrial contraction was unchanged in healthy lowlanders after ascending 4,100 m within 7 d. Similarly, Sareban et al identified that left atrial contraction failed to increase after ascension and pointed out that it cannot compensate for SV reductions. Intriguingly, a recent study observed disproportionate decreases in LV mass compared with reductions in total body weight after 2 weeks of high-altitude exposure. They hypothesized that the loss of cardiac mass was likely similar to the adaptive wasting of skeletal muscle during hypoxic exposure, attenuating oxygen demand in metabolically active tissue. Furthermore, studies have revealed an altered energy metabolism with a decreased ratio of phosphocreatine/adenosine triphosphate in lowlanders during acute hypoxia and Sherpa people with chronic hypoxia.[59,61] The altered energetics at high altitude imply decreased energy reserves and the loss of cardiac mitochondrial mass, likely representing a universal hypoxia response.
Stembridge et al further explored the myocardial mechanical reserve during exercise at high altitude. Exercise at sea level always lead to an increased SV to satisfy oxygen consumption through an increase in LV end-diastolic volume. However, although LV systolic function was enhanced during exercise at high altitude, the increase in SV was limited, and LV end-diastolic volume failed to increase. Despite an enhancement of diastolic relaxation during exercise at high altitude, assessed by diastolic untwisting velocity, it could not maintain LV diastolic filling. Thus, although hypoxia could not impair LV systolic function, the capacity of SV to increase during exercise at high altitude was restricted due to limited diastolic filling.
4. RV function at high altitude
High-altitude exposure should have predominant effects on the RV, because of an elevated afterload due to pulmonary vasoconstriction. Additionally, hypoxia itself contributes to the alteration of RV function at high altitudes through several molecular pathways, including oxidative stress, protein kinase activation, inflammation, and fibrosis. However, the adaptive performance of RV to high altitude is controversial. Huez et al evaluated RV function in 25 healthy volunteers after 90 min of oxygen inspiration at an altitude of 4,500 m. The study observed unchanged tricuspid annular plane systolic excursion (TAPSE) and tricuspid S wave after acute hypoxia exposure, suggesting preserved RV systolic function. Similarly, Boos et al reported that tricuspid S wave remained normal in 19 healthy subjects, both at rest and during exercise at high altitudes from 3,440 to 5,150 m. Nevertheless, some studies observed different results on RV performance at high altitudes. Our previous studies found decreased RV fractional area change (FAC) in healthy male lowlanders after 7-day exposure to 4,100 m. Likewise, Stembridge et al reported that TAPSE and peak RV longitude strain were lower after nearly 10 d of exposure to 5,050 m. Our study demonstrated the association between impaired RV systolic function and elevated PAP, which likely partly explained the differences among studies on RV function under acute high-altitude exposures. The decreased RV systolic function could reduce the volume of blood returning to the left heart, which in turn could contribute to the decreased SV at high altitudes. Interestingly, our previous study described that high-altitude-induced RV dyssynchrony during RV systole, and found it was related with declined oxygen saturation as well as elevated PAP, implying an potential mechanics underlying decreased RV systolic function at high altitude. Additionally, another study by us demonstrated the relation between impaired RV function and RV outflow tract notch formation using Doppler echocardiography at high altitude, which might provide a new echocardiographic sign to identify impaired RV function at high altitude. For acclimatized highlanders, although lower TAPSE and tricuspid S wave were observed, they did not necessarily indicate impaired RV contraction under lifetime hypoxia. It should be noted that despite the lower RV systolic function in healthy highlanders at rest, it could increase during exercise, further suggesting that RV systolic function adapts well to chronic hypoxia.
As for diastolic function, decreased tricuspid flow E/A and prolonged isovolumic relaxation time were observed in RV, as was the case for LV mechanics.[10,55] Stembridge et al unexpectedly reported no significant differences in RV longitude peak diastolic strain rate between lowlanders at sea level, lowlanders at high level, and native highlanders, possibly implying a good tolerance of RV relaxation to whether acute or chronic hypoxia. Studies on right atrial performance under high-altitude exposure showed different results. Sareban et al reported that right atrial contraction increased after a rapid ascent to 4,559 m, to compensate for the RV overload. However, in our study, we found a decline in right atrial contraction after an ascent to 4,100 m. We speculated that the discrepancy might be partly derived from different degrees of pulmonary vasoconstriction and RV function at high altitudes. Furthermore, the increased right atrial dyssynchrony under acute high-altitude exposure might help explain impaired right atrial contraction.
Chronic high-altitude exposure induces persistent hypoxic PH, causes a long-term overload to the right heart, and possibly leads to RV dilation and hypertrophy, even right heart failure, described as high altitude heart disease (HAHD). HAHD was first reported and defined by Chinese researchers. HAHD generally occurs in immigrants, rather than lifetime inhabitants, at high altitudes above 3,000 m. HAHD is categorized as a chronic high-altitude disease with prominent PH and is named high-altitude PH by the International Society for Mountain Medicine. The severity of RV hypertrophy should be attributed to the pulmonary vasoconstrictor response, vascular resistance, and absolute altitude level. Among them, pulmonary vasoconstriction highly depends on genetic susceptibility, and is strong in less than 1% of cases, which induce severe PH and right heart failure.[75,76] The increase in PAP during exercise in patients with chronic mountain sickness was 2-fold higher than that in healthy highlanders. Additionally, tricuspid S wave in chronic mountain sickness patients was lower than that in healthy highlanders, both at rest and during exercise, implying the impairment of RV systolic function.
Descent to lower altitudes should be the best treatment for patients with HAHD; however, it usually cannot be achieved for personal or economic reasons. Oxygen supplementation, hyperbaric chambers, and medicines to improve symptoms have yet to be common treatments for high altitude-related diseases. Moreover, the medicines inhibiting pulmonary vasoconstriction described above might be potential therapies for HAHD, although their efficiency needs to be validated. Recently, Smith et al reported that hypoxic PH was associated with iron level. They further demonstrated that iron supplementation reduced hypoxia-induced increments in PAP, and reversed approximately 40% of the pulmonary hypertensive response in lowlanders after acute high-altitude exposure. Accordingly, iron supplementation can be considered as a potential therapeutic option for HAHD. Nevertheless, effective targets for HAHD intervention have not been completely elucidated so far and need to be further explored.
5. Clinical recommendations
Acclimatization to high altitude brings an excessive load on the cardiovascular system, whereas its actual risk for individuals with preexisting cardiovascular diseases is still debated. Schmid et al studied 29 patients with stable heart failure (New York Heart Association (NYHA) Class II) during short-term exposure to 3,454 m and concluded that no patients had to immediately return to lower altitudes. Even in patients with severe heart failure (NYHA Class III–IV), no episodes of angina, electrocardiographic evidence of arrhythmias, or ischemia were recorded during cardiopulmonary exercise at simulated 3,000 m. All heart failure patients were recommended a slow ascent to high altitude, and to be prudent not to exceed 300–500 m per day, as recommended for healthy travelers. Coronary blood flow increases during acute high-altitude exposure in healthy subjects due to coronary vasodilation, and rises further during exercise at 4,500 m, suggesting a good tolerance of coronary flow reserve in healthy subjects. However, individuals with coronary artery disease might encounter a limitation in their increment of coronary flow at high altitude, given the basal increased coronary flow. Schmid et al reported that although maximum work capacity decreased at 3,454 m in myocardial ischemic patients with low risk, no signs of ischemia or arrhythmias were noted during exercise. Wyss et al observed that myocardial blood flow during exercise succeeded to increase at 2,500 m, but failed at 4,500 m in patients with coronary artery diseases. These patients are recommended to be cautious about physical exercise when ascending to moderate altitudes. Additionally, patients with acute coronary syndromes and revascularization should consider waiting for at least 6 months before high-altitude exposure. In hypertensive patients, a moderate increase in blood pressure was observed with high-altitude exposure, the same as that in healthy individuals. Individuals with well-controlled hypertension are considered able to ascend to high altitudes with adequate medical therapy, while patients with uncontrolled hypertension are not recommended high-altitude exposures. However, most studies on cardiovascular disease patients upon high-altitude exposure were small-scale, and actual risk needs further verification.
Overall, this article briefly reviews physiological adaptation and pathological mechanisms of the heart under high-altitude exposure, and may help in the transition from experience to evidence, and further understand the challenge of life for human beings at high altitude. We discussed the clinical management of medical complications related to high altitude, providing practical suggestions for medical aid at high altitudes as far as possible and giving potential directions for advancements in high-altitude medicine. However, it should be acknowledged that studies in this field are difficult to conduct due to hypobaric hypoxia environment and economical restrictions at high altitude. To date, most studies have been limited to small sample sizes, included young healthy subjects, and have lacked a randomized controlled design. Furthermore, such studies are generally not fully comparable because of differences in altitude levels, ascending speeds, physical activity, climate change, and so on. Although cardiac performance under high altitude has been well described, certain controversies remain. Studies with larger cohorts and a randomized design should be conducted to draw robust conclusions. Furthermore, future work should be focused on developing strategies to better acclimatize individuals to high altitudes and prevent high altitude-related diseases, especially susceptible ones.
This work was supported by grants from the National Natural Science Foundation of China (81730054) and Military Logistics Research Project, PLA (BLJ18J007)
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