Pub Date: Thursday, Sep 09, 2021
Author: Erik R. Swenson, MD
Affiliation: Pulmonary, Critical Care and Sleep Medicine, University of Washington, VA Puget Sound Health Care System
As the popularity of recreation and travel to high altitude regions of the world continues to increase along with the growing number of patients living longer with heart disease, more and more internists and cardiologists will be faced with how best to advise their patients wishing to work or vacation in the alpine or high plains environment. Knowledge of how the ambient hypoxia, along with the cold and other stressful aspects of high altitude, affect the heart and circulation particularly with exercise are critical to successful evaluation, counseling, preparation, and response to problems and deterioration should they develop when at high altitude. These important matters are taken up ably and succinctly in the American Heart Association scientific statement by Cornwell et al1, an august group of cardiologists, many of whom have done considerable research at high altitude in healthy subjects and patients with cardiovascular disease.
They begin with a brief review of the physiologic changes with high altitude exposure relevant to the cardiovascular system, which in the broadest sense must include the brain, heart, lungs, blood, and vasculature which act to blunt the extent of arterial hypoxemia, reduction of tissue oxygen delivery and decrease in aerobic exercise capacity in healthy persons. Many of these short-term adaptations, including greater cardiac output and ventilation, in addition to changes in vascular resistance in the pulmonary and systemic circulation may present considerable stress on the heart and lungs of these patients and limit physical activity compared to healthier persons. The degree to which these adaptive changes and demands can be tolerated are tied to the altitude and time at altitude. The pace of adaptation in each organ system differs such that what occurs acutely in hours to a few days will change and sometimes in a directionally opposite manner with longer time at altitude, as observed with blood pressure and cardiac output.
The common conditions of coronary artery disease, systemic hypertension, arrhythmias, sudden cardiac death, heart failure, syncope and autonomic instability, sleep apnea and pulmonary hypertension are discussed in sufficient detail based upon the best available data provided in the reference list for further reading, including a similar statement published in the European Heart Journal in 2018.2 Practical advice for each of these conditions in terms of assessing and achieving stability is offered along with specific pre-trip testing to recommend safe ascent rates and maximum altitude, which in some cases is the same advice given to healthy people so as to allow normal adequate acclimatization3 and avoid acute mountain sickness (AMS), high altitude pulmonary edema and cerebral edema.
In addition to the expert advice for the conditions addressed in this AHA Scientific Statement, I wish to offer a few further additions and perspectives relating to how people with heart disease will fare well or poorly at high altitude. The first is that the kidneys and renal function are altered by hypoxia in healthy persons and in those with renal disease4, which given the intimate link of the kidneys and heart in cardiovascular disease may have some bearing on patients with heart disease. Some people experience changes in urinary output from considerable diuresis to diminished urination and fluid retention in the first day at high altitude arising from a balance of hypoxic peripheral chemoreceptor stimulation that drives increase ventilation (diuresis) and sympathetic nervous system activation (anti-diuresis). This generally abates within a day or so, but those on diuretics may need to be forewarned.
Another matter addressed in the statement is that of iron deficiency with or without anemia. The erythropoietic response to hypoxia requires iron and its deficiency may not permit one of the slower but still important compensations to high altitude to increase blood oxygen carrying capacity. Additionally, hypoxic pulmonary vasoconstriction (HPV) is greater with iron deficiency5 so that those with any form of pulmonary hypertension, either WHO group 2 (pulmonary hypertension with left heart disease) or other forms, may risk greater right ventricular strain and reductions in cardiac output with exertion. This concern has been diminished recently in a group of patients with mild-moderately severe pulmonary arterial hypertension (WHO group 1 and 4) who did not have any further elevation of PA pressure at rest or with exercise with inhalation of 15% oxygen equivalent to an altitude of roughly 2,000 m.6 Whether higher altitude and lower inspired PO2 can be tolerated without greater pulmonary hypertension remains to be determined. The whole story about iron and altitude continues to evolve, and importantly patients with group 2 disease have yet to be studied for benefits above and beyond the direct effect to the myocardium and skeletal muscle.
Some healthy people develop mild subclinical pulmonary edema at high altitude7 which may be related to elevation of PA pressures from strong HPV. To the extent that this might occur in patients with heart failure has not been studied, but it would be more problematic in these individuals. Inhaled albuterol, a beta 2-adrenergic agonist, reduces extravascular lung water in patients with HFrEF and increases lung diffusing capacity8 by stimulation of pulmonary lymphatic fluid clearance and active alveolar epithelial sodium and water reabsorption.10 In patients with HFpEF, inhaled albuterol increases cardiac output reserve, lowers pulmonary vascular resistance, left atrial and pulmonary artery pressure during exercise, without causing tachycardia.9 Inhaled beta-2 agonists have not been tested at altitude in patients with heart failure, but these effects noted in normoxia may be of benefit and worthy of study.
Hypoxia and high altitude have complex effects on coagulation that in aggregate may pose a risk for venous thromboembolism.10, 11 Arterial and coronary arterial thrombosis may also be heightened with hypoxia and exercise12 perhaps as a result of platelet activation.13 Thus, optimization of aspirin and statin therapy is advised.14
Finally, while healthy people may feel out of sorts and inconvenienced for the first couple of days upon arrival at altitude, the stress of headache, nausea, and other symptoms of AMS in patients with cardiovascular diseases may not be as benign. While patients with cardiovascular disease have not been studied in any formal fashion, prevention of AMS is highly recommended, either by slow and staged ascent or pharmacologically.3 In this latter regard, acetazolamide at low doses for AMS prevention may be superior to other drugs including non-steroidal anti-inflammatory drugs and corticosteroids, due to its stimulation of ventilation to raise arterial PO215, lower systemic blood pressure16, diminish platelet activation17, enhance hypoxic subendocardial viability18, reduce sleep-related central apnea19 and act as a mild diuretic.15 Acetazolamide has a long safety record in patients with heart disease20 and in fact, was the first and only safe orally effective diuretic for congestive heart failure when it became available in the 1950s before the advent of loop diuretics and thiazides, and is still used to counter the metabolic alkalosis sometimes generated with loop diuretic use.21
Cornwell WK 3rd, Baggish AL, Bhatta YKD, Brosnan MJ, Dehnert C, Guseh JS, Hammer D, Levine BD, Parati G, Wolfel EE; on behalf of the American Heart Association Exercise, Cardiac Rehabilitation, and Secondary Prevention Committee of the Council on Clinical Cardiology; and Council on Arteriosclerosis, Thrombosis and Vascular Biology. Clinical implications for exercise at altitude among individuals with cardiovascular disease: a scientific statement from the American Heart Association. J Am Heart Assoc. 2021;10:e023225. DOI: 10.1161/JAHA.121.023225
- Cornwell WK, Baggish AL, Bhatta YKD, Brosnan MJ, Dehnert C, Guseh JS, Hammer D, Levine BD, Parati G, Wolfel EE. Clinical implications for exercise at altitude among individuals with cardiovascular disease: a scientific statement on behalf of the American Heart Association. J Am Heart Assoc. 2021;10:e023225. DOI: 10.1161/JAHA.121.023225.
- Parati G, Agostoni P, Basnyat B, Bilo G, Brugger H, Coca A, Festi L, Giardini G, Lironcurti A, Luks AM, Maggiorini M, Modesti PA, Swenson ER, Williams B, Bärtsch P, Torlasco C. Clinical recommendations for high altitude exposure of individuals with pre-existing cardiovascular conditions: A joint statement by the European Society of Cardiology, the Council on Hypertension of the European Society of Cardiology, the European Society of Hypertension, the International Society of Mountain Medicine, the Italian Society of Hypertension and the Italian Society of Mountain Medicine. Eur Heart J. 2018;39:1546-1554.
- Bärtsch P, Swenson ER. Clinical practice: Acute high-altitude illnesses. N Engl J Med. 2013; 368:2294-302.
- Luks AM, Johnson RJ, Swenson ER. Chronic kidney disease at high altitude. J Am Soc Nephrol. 2008;19:2262-71.
- Willie CK, Patrician A, Hoiland RL, Williams AM, Gasho C, Subedi P, Anholm J, Drane A, Tymko MM, Nowak-Flück D, Plato S, McBride E, Varoli G, Binsted G, Eller LK, Reimer RA, MacLeod DB, Stembridge M, Ainslie PN. Influence of iron manipulation on hypoxic pulmonary vasoconstriction and pulmonary reactivity during ascent and acclimatization to 5050 m. J Physiol. 2021;599:1685-1708.
- Schneider SR, Mayer LC, Lichtblau M, Berlier C, Schwarz EI, Saxer S, Furian M, Bloch KE, Ulrich S. Effect of Normobaric Hypoxia on Exercise Performance in Pulmonary Hypertension: Randomized Trial. Chest. 2021;159:757-771.
- Pratali L. Right Heart-Pulmonary Circulation at High Altitude and the Development of Subclinical Pulmonary Interstitial Edema. Heart Fail Clin. 2018;14:333-337.
- Taylor BJ, Snyder EM, Richert ML, Wheatley CM, Chase SC, Olson LJ, Johnson BD. Effect of beta(2)-adrenergic receptor stimulation on lung fluid in stable heart failure patients. J Heart Lung Transplant. 2017: 36:418-426.
- Reddy YNV, Obokata M, Koepp KE, Egbe AC, Wiley B, Borlaug BA. The beta-Adrenergic Agonist Albuterol Improves Pulmonary Vascular Reserve in Heart Failure with Preserved Ejection Fraction. Circ Res. 2019;124:306-314.
- DeLoughery TG. Anticoagulation Considerations for Travel to High Altitude. High Alt Med Biol. 2015;16:181-5.
- Trunk AD, Rondina MT, Kaplan DA. Venous Thromboembolism at High Altitude: Our Approach to Patients at Risk. High Alt Med Biol. 2019;20:331-336.
- Basavarajaiah S, O'Sullivan M. Physical exertion at high altitude--another risk factor for coronary stent thrombosis? J Invasive Cardiol. 2013;25:E66-8.
- Paterson GG, Young JM, Willson JA, Graham CJ, Dru RC, Lee EW, Torpey GS, Walmsley SR, Chan MV, Warner TD, Baillie JK, Thompson AAR. Hypoxia Modulates Platelet Purinergic Signaling Pathways. Thromb Haemost. 2020;120:253-261.
- 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.
- Swenson ER. Pharmacology of acute mountain sickness: old drugs and newer thinking. J Appl Physiol. 2016;120:204-15.
- Salvi P, Revera M, Faini A, Giuliano A, Gregorini F, Agostoni P, Becerra CG, Bilo G, Lombardi C, O'Rourke MF, Mancia G, Parati G. Changes in subendocardial viability ratio with acute high-altitude exposure and protective role of acetazolamide. Hypertension. 2013;61:793-9.
- Agbani EO, Zhao X, Williams CM, Aungraheeta R, Hers I, Swenson ER, Poole AW. Carbonic Anhydrase Inhibitors suppress platelet procoagulant responses and in vivo thrombosis. Platelets. 2020;31:853-859.
- Parati G, Revera M, Giuliano A, Faini A, Bilo G, Gregorini F, Lisi E, Salerno S, Lombardi C, Ramos Becerra CG, Mancia G, Salvi P. Effects of acetazolamide on central blood pressure, peripheral blood pressure, and arterial distensibility at acute high altitude exposure. Eur Heart J. 2013;34:759-66.
- Bloch KE, Latshang TD, Ulrich S. Patients with Obstructive Sleep Apnea at Altitude. High Alt Med Biol. 2015;16:110-6.
- Swenson ER. Carbonic anhydrase and the heart. Cardiologia. 1998;42:453-62.
- Mullens W, Verbrugge FH, Nijst P, Martens P, Tartaglia K, Theunissen E, Bruckers L, Droogne W, Troisfontaines P, Damman K, Lassus J, Mebazaa A, Filippatos G, Ruschitzka F, Dupont M. Rationale and design of the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial. Eur J Heart Fail 2018;20:1591-1600.
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