Exposure to hypoxia at altitude elicits a physiologic response from the cardiovascular and pulmonary systems that may further compromise patients previously infected and injured by coronavirus-19 (COVID-19). Among healthy (non-infected) individuals, the reduction in atmospheric pressure and partial pressure of oxygen reduces the driving pressure for gas exchange in the lungs, as well as blood oxygen content.¹ This hypoxic stimulus activates peripheral chemoreceptors,² increasing sympathetic neural activity in proportion to the degree of hypoxia.^1,3,4 The augmentation of sympathetic tone, combined with vagal withdrawal (from hyperventilation), dominates the acute cardiovascular response to hypoxia at altitude⁵ with acute increases in heart rate, stroke volume, cardiac output, and total peripheral resistance. Within the lungs, minute ventilation increases as a result of hypoxia.⁴ Vasoconstriction of the pulmonary vasculature occurs in response to reductions in partial pressure of oxygen in the alveoli. The result is an increase in pulmonary arterial pressures and pulmonary vascular resistance, termed hypoxic pulmonary vasoconstriction, which begins within minutes of exposure to hypoxia.^{4, 6-8}

Because of this normal physiologic response to hypoxia, individuals with a history of COVID-19 infection, particularly those sick enough to require hospitalization and suffer both pulmonary and cardiac injury, may be at heightened risk of adverse events during mountainous sojourns, depending on the presence and severity of cardiovascular and pulmonary sequelae. The American Heart Association (AHA) recently provided recommendations on assessments for patients with cardiovascular and pulmonary disease prior to travel to altitude,⁹ and the presence of these comorbidities may also contribute to an increase in risk. Finally, mountainous excursions involving exercise will worsen the hypoxic stimulus, particularly since the increased cardiac output during exercise reduces red blood cell transit time through the pulmonary arterial bed, limiting time for gas exchange to occur in an environment that is relatively oxygen-deplete compared to sea-level. Therefore, pre-travel assessments may be necessary to counsel and risk-stratify patients with history of COVID-19 infection.⁶

Cardiovascular and Pulmonary Sequelae of COVID-19

Left ventricular (LV) systolic function is generally preserved following COVID-19 infection,¹⁰ with only a small minority of individuals (<3%) showing evidence of reduced ejection fraction.¹¹ Among patients with history of hospitalization for COVID-19 and persistent cardiac symptoms (chest pain, palpitations), abnormalities on cardiac magnetic resonance imaging (MRI) including myocardial edema and/or late gadolinium enhancement were reported in 58% of such patients.¹² Among hospitalized individuals with elevated high-sensitivity troponin, 45% had evidence of myocarditis on cardiac MRI.¹³ However, COVID-19 myocarditis is extremely uncommon among non-hospitalized individuals¹⁴ and young athletes.^14-16 Among professional athletes (N=789) undergoing mandatory return-to-play cardiac screening following COVID-19 infection, only five (0.6%) had cardiac MRI findings suggestive of myocarditis or pericarditis.¹⁵ Right ventricular (RV) function, as determined by tricuspid annular plane systolic excursion on echocardiography, is generally preserved.^10,17 However, among patients hospitalized for moderate infection, up to 10% had RV dysfunction as determined by global longitudinal strain, which persisted 2 months following discharge.¹⁸

Mild impairments in diffusion capacity for carbon monoxide (DLCO) have also been reported following COVID-19.¹⁷ In a series of patients evaluated 6 weeks following hospitalization for severe COVID-19 infection but not requiring mechanical ventilation, pulmonary function tests were normal except for a reduced DLCO (77%).¹⁷ Among patients requiring mechanical ventilation, however, DLCO was severely reduced (51±13%) 6 weeks following hospital discharge.¹⁹ While noninvasive measures of pulmonary arterial pressures are typically normal following COVID-19, up to 10% of individuals may develop pulmonary hypertension.¹¹ Patients hospitalized with COVID-19 are at an increased risk of venous thromboembolism, which when present, may also reduce tolerance to hypoxia. While lung volumes typically normalize after infection,⁶ it is unknown whether persistent reductions in lung volumes increase the risk of high altitude pulmonary edema. Thus, depending on the severity of the acute illness, residual abnormalities of cardiopulmonary function may exist after COVID-19 infection.

Exercise at Altitude Following COVID-19

While resting oxygen saturation levels at sea-level are typically normal following COVID-19 infection,²⁰ hypoxemia during exercise results from impairments in gas exchange, which is further exacerbated at altitude where there is a reduction in the sea-level equivalent of the fraction of inspired oxygen (FiO₂).⁹ For example, at moderate altitudes (2,000-3,000m), the FIO₂ equivalent is approximately 15-16%, and at high altitudes (3,000-5,500m), the FIO₂ equivalent declines further to approximately 12-13%. In healthy individuals, these reductions in FIO₂ at moderate and high altitudes reduce exercise capacity as determined by peak oxygen uptake, by approximately 8% and approximately 30%, respectively.⁹ For individuals with cardiovascular and pulmonary sequelae following COVID-19, further decrements in exercise capacity are anticipated, along with an inability to tolerate hypoxic environments, particularly among patients with ongoing myocardial inflammation and/or abnormalities in pulmonary function such as reduced DLCO. In the presence of ongoing inflammation, the combination of hypoxia and exercise may also predispose to arrhythmias.

Risk Assessment Prior to Altitude Travel

Previously healthy and asymptomatic individuals, as well as symptomatic patients treated conservatively and who fully recover, require no further evaluation following COVID-19 prior to altitude travel.⁶ However, patients with persistent symptoms, as well as those with severe infection requiring intensive care and/or with evidence of myocarditis, should have pre-travel cardiovascular and pulmonary testing for risk stratification and awareness of activity restrictions.⁶ Testing should include laboratory evaluation (high-sensitivity troponin, brain natriuretic peptide), imaging with echocardiography, and cardiac MRI when persistent myocardial inflammation is suspected. Cardiopulmonary exercise testing should be considered to delineate mechanisms and severity of impairments in exercise capacity. For patients with evidence of ongoing inflammation and/or clinically significant reductions in DLCO, travel to hypoxic environments may need to be delayed until resolution of the sequelae of infection. Patients with abnormal exercise responses during cardiopulmonary exercise testing at sea-level (e.g., moderate-severely reduced peak oxygen uptake; ventilatory inefficiency) should anticipate further reductions at altitude, the severity of which may limit exercise tolerance upon arrival to the location of interest. The presence of these abnormalities on pre-travel assessments may warrant referral to specialists with expertise in environmental medicine to risk-stratify patients and provide additional counseling on travel plans through shared decision making with patients and referring providers.

Summary Thoughts

Luks and Grissom recently summarized the cardiovascular and pulmonary sequelae of COVID-19 infection and associated implications of hypoxic exposure during mountainous sojourns among patients with history of infection.⁶ As they nicely emphasize, travel to altitude involves a physiologic response to hypoxia, which increases demands on the cardiovascular and pulmonary systems. These demands may be exacerbated based on the presence and severity of sequelae of COVID-19 infection. Knowledge regarding severity of the infection, combined with presence of ongoing symptoms, knowledge of travel plans (e.g., location/duration and altitude of travel, as well as activities planned), and patient comorbidities, is necessary for pre-travel risk stratification. Additional testing may be necessary to verify recovery of the cardiovascular and pulmonary symptoms, ensuring that risks are minimized, and travel is safe.

References

1. Levine BD. Going high with heart disease: the effect of high altitude exposure in older individuals and patients with coronary artery disease. High Alt Med Biol 2015;16:89-96.
2. Heistad DD, Abboud FM. Circulatory adjustments to hypoxia. Circulation 1980;61:463-70.
3. Hansen J, Sander M. Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia. J Physiol 2003;546:921-29.
4. Bärtsch P, Gibbs JS. Effect of altitude on the heart and the lungs. Circulation 2007;116:2191-2202.
5. Baggish AL, Wolfel EE, Levine BD. Cardiovascular system. High Altitude 2014:103-39.
6. Luks AM, Grissom CK. Return to high altitude after recovery from coronavirus disease 2019. High Alt Med Biol 2021;22:119-27.
7. Dunham-Snary KJ, Wu D, Sykes EA, et al. Hypoxic pulmonary asoconstriction: from molecular mechanisms to medicine. Chest 2017;151:181-92.
8. Talbot NP, Balanos GM, Dorrington KL, Robbins PA. Two temporal components within the human pulmonary vascular response to approximately 2 h of isocapnic hypoxia. J Appl Physiol (1985) 2005;98:1125-39.
9. Cornwell WK 3rd, Baggish AL, Deo Bhatta YK, et al. Clinical Implications for exercise at altitude among individuals with cardiovascular disease: a scientific statement from the American Heart Association. J Am Heart Assoc 2021;Sept 9:[Epub ahead of print].
10. Catena C, Colussi G, Bulfone L, Da Porto A, Tascini C, Sechi LA. Echocardiographic comparison of COVID-19 patients with or without prior biochemical evidence of cardiac injury after recovery. J Am Soc Echocardiogr 2021;34:193-95.
11. Sonnweber T, Sahanic S, Pizzini A, et al. Cardiopulmonary recovery after COVID-19: an observational prospective multicentre trial. Eur Respir J 2021;Apr 29;[Epub ahead of print].
12. Huang L, Zhao P, Tang D, et al. Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging. JACC Cardiovasc Imaging 2020;13:2330-39.
13. Knight DS, Kotecha T, Razvi Y, et al. COVID-19: myocardial injury in survivors. Circulation 2020;142:1120-22.
14. Clark DE, Parikh A, Dendy JM, et al. COVID-19 myocardial pathology evaluation in athletes with ardiac magnetic resonance (COMPETE CMR). Circulation 2021;143:609-12.
15. Martinez MW, Tucker AM, Bloom OJ, et al. Prevalence of inflammatory heart disease among professional athletes with prior COVID-19 infection who received systematic return-to-play cardiac screening. JAMA Cardiol 2021;6:745-52.
16. Rajpal S, Tong MS, Borchers J, et al. Cardiovascular nagnetic resonance findings in competitive athletes ecovering from COVID-19 infection. JAMA Cardiol 2021;6:116-18.
17. Daher A, Balfanz P, Cornelissen C, et al. Follow up of patients with severe coronavirus disease 2019 (COVID-19): pulmonary and extrapulmonary disease sequelae. Respir Med 2020;Oct 20:[Epub ahead of print].
18. Tudoran C, Tudoran M, Lazureanu VE, et al. Evidence of pulmonary hypertension after SARS-CoV-2 infection in subjects without previous significant cardiovascular pathology. J Clin Med 2021;10:199.
19. Finney LJ, Doughty R, Lovage S, et al. Lung function deficits and symptom burden in survivors of COVID-19 requiring mechanical ventilation. Ann Am Thorac Soc 2021;18:1740-43.
20. Lerum TV, Aalokken TM, Bronstad E, et al. Dyspnoea, lung function and CT findings 3 months after hospital admission for COVID-19. Eur Respir J 2021;Apr 29:[Epub ahead of print].

Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, COVID-19 Hub, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Pericardial Disease, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Sports and Exercise Cardiology, Vascular Medicine, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Pulmonary Hypertension, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Hypertension, Sports and Exercise and ECG and Stress Testing, Sports and Exercise and Imaging

Keywords: Altitude, Exercise Tolerance, Stroke Volume, Carbon Monoxide, Gadolinium, Natriuretic Peptide, Brain, Contrast Media, Hypertension, Pulmonary, Exercise Test, Vasoconstriction, Oxygen, Heart Rate, Partial Pressure, Hyperventilation, Venous Thromboembolism, Myocarditis, Coronavirus, Respiration, Artificial, Patient Discharge, Troponin, Pulmonary Edema, Environmental Medicine, American Heart Association, Specialization, Laboratories, Arterial Pressure, Decision Making, Shared, Acute Disease, COVID-19, Return to Sport, Lung, Vascular Resistance, Lung Volume Measurements, Magnetic Resonance Imaging, Arrhythmias, Cardiac, Echocardiography, Atmospheric Pressure, Chest Pain, Athletes, Pericarditis, Edema, Erythrocytes, Risk Assessment, Critical Care, Inflammation, Inflammation, Referral and Consultation, Counseling, Hospitals, Sports

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