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Evolution of Pulmonary Hypertension During Severe Sustained Hypoxia

2020; Lippincott Williams & Wilkins; Volume: 141; Issue: 18 Linguagem: Inglês

10.1161/circulationaha.119.045192

1524-4539

Fabian Hoffmann, Ulrich Limper, Vlad G. Zaha, Hannes Reuter, Leonora Zange, Jeanette Schulz‐Menger, Marc Hein, Stephan Baldus, Benjamin D. Levine, Jens Jordan, Jens Tank,

Congenital Heart Disease Studies

HomeCirculationVol. 141, No. 18Evolution of Pulmonary Hypertension During Severe Sustained Hypoxia Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBEvolution of Pulmonary Hypertension During Severe Sustained Hypoxia Fabian Hoffmann, MD, Ulrich Limper, MD, Vlad G. Zaha, MD, PhD, Hannes Reuter, MD, Leonora Zange, MD, Jeanette Schulz-Menger, MD, Marc Hein, MD, Stephan Baldus, MD, Benjamin D. Levine, MD, PhD, Jens Jordan, MD and Jens Tank, MD Fabian HoffmannFabian Hoffmann Fabian Hoffmann, MD, Department of Cardiovascular Aerospace Medicine, German Aeropsace Center, Linder Hoehe, 51147 Cologne, Germany. Email E-mail Address: [email protected] or E-mail Address: [email protected] https://orcid.org/0000-0002-3199-9924 Institute of Aerospace Medicine, German Aerospace Center, Cologne (F.H., U.L., J.J., J.T.). Department of Internal Medicine III (F.H., H.R., S.B.), University of Cologne, Germany. , Ulrich LimperUlrich Limper Institute of Aerospace Medicine, German Aerospace Center, Cologne (F.H., U.L., J.J., J.T.). Department of Anaesthesiology and Intensive Care Medicine, Cologne-Merheim Medical Center, University of Witten Herdecke, Germany (U.L.). , Vlad G. ZahaVlad G. Zaha Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas (V.G.Z., B.D.L.). , Hannes ReuterHannes Reuter Department of Internal Medicine III (F.H., H.R., S.B.), University of Cologne, Germany. Department of Internal Medicine and Cardiology, Evangelical Clinic Weyertal, Cologne, Germany (H.R.). , Leonora ZangeLeonora Zange Working Group on Cardiovascular Magnetic Resonance, Experimental and Clinical Research Center –a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany (L.Z., J.S.-M.). Department of Cardiology and Nephrology, HELIOS Hospital Berlin-Buch, Germany (L.Z., J.S.-M.). , Jeanette Schulz-MengerJeanette Schulz-Menger Working Group on Cardiovascular Magnetic Resonance, Experimental and Clinical Research Center –a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany (L.Z., J.S.-M.). Department of Cardiology and Nephrology, HELIOS Hospital Berlin-Buch, Germany (L.Z., J.S.-M.). , Marc HeinMarc Hein Department of Anaesthesiology, Medical Faculty, RWTH Aachen University, Germany (M.H.). , Stephan BaldusStephan Baldus Department of Internal Medicine III (F.H., H.R., S.B.), University of Cologne, Germany. , Benjamin D. LevineBenjamin D. Levine Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas (V.G.Z., B.D.L.). Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital, Dallas (B.D.L.). , Jens JordanJens Jordan Institute of Aerospace Medicine, German Aerospace Center, Cologne (F.H., U.L., J.J., J.T.). Aerospace Medicine (J.J.), University of Cologne, Germany. and Jens TankJens Tank Institute of Aerospace Medicine, German Aerospace Center, Cologne (F.H., U.L., J.J., J.T.). Originally published4 May 2020https://doi.org/10.1161/CIRCULATIONAHA.119.045192Circulation. 2020;141:1504–1506Hypoxia-induced pulmonary hypertension occurs in healthy individuals ascending to high altitude, although with individual variability. In the short term, increases in pulmonary pressure predispose to high-altitude pulmonary edema1,2; in some high-altitude populations, long-term exposure elicits severe pulmonary hypertension, right ventricular failure, or chronic mountain sickness. Yet, substantially increased right ventricular afterload may be well tolerated in healthy people, particularly with short-term high-altitude exposure. Both extremes were observed in sustained hypobaric hypoxia corresponding to >6000-m altitude.3 Whether hypoxia-induced pulmonary hypertension progresses or adapts with sustained hypoxia is unknown. We assessed human cardiopulmonary adaptation within a pilot study applying normobaric hypoxia corresponding to ≈7000-m altitude for several weeks, akin to previous murine studies on myocardial regeneration.4At the German Aerospace Center: envihab facility, we enrolled 2 healthy professional mountaineers. Subject A was male and 57 years of age with extensive experience with >8000-m altitude. Subject B was female and 49 years of age with experience with >5000-m altitude. The protocol was approved by the Northrhine Medical Association ethics committee and conducted according to the Declaration of Helsinki (DRKS00013772) after written informed consent was obtained.After 1 week preacclimatization at 4559-m altitude in the Alps, subjects entered the hypoxia module. We decreased oxygen stepwise over 3 weeks by adding nitrogen from 13.5% to a minimum of 8%, corresponding to 3500- and 7112-m altitude. We included a recovery phase, akin to high-altitude mountaineering, followed by 2 weeks of stable hypoxia (8.5% oxygen during daytime, 8.8% during nighttime). Then, hypoxia was gradually reduced over 36 hours (Figure [A]). Subjects were under continuous medical surveillance.Download figureDownload PowerPointFigure. Evolution of pulmonary hypertension during severe sustained hypoxia.A, Oxygen and corresponding altitude profile: study progress and acclimatization profile. Oxygen levels with corresponding altitudes at each study day during day (D) and nighttime (N). Similar to an ascent in high altitude, a recovery phase was included after 3 weeks of acclimatization before subjects entered the stable hypoxia phase (broken lines) with 8.5% oxygen during daytime and 8.8% at night. Lake Louise scores (LLSs) indicated acute mountain sickness during the acclimatization phase only with a peak value of 10 of 16. Green circles indicate magnetic resonance imaging (MRI) examinations; blue triangles, echocardiography. B, Normobaric hypoxia induces pulmonary artery (PA) hypertension. Individual data of right ventricular to atrial systolic pressure gradient (RVAsPG) during the study (blue, Subject A; red, Subject B). C, Short axis with D-shaped left ventricle at 8% O2, Subject B. Left, Echocardiographic image of the end-systolic short axis at the papillary muscle level in Subject B on day 21 at 8.0% oxygen and an RVAsPG of 55 mm Hg. Arrow indicates septal flattening with left ventricular deformation resulting in an elevated systolic eccentricity index. Right, Cardiac MRI (CMR) cine-loop image at the corresponding midventricular short-axis level. D, Normobaric hypoxia induces PA dilation and a decrease in distensibility. Individual data of PA area (solid lines) and distensibility (dotted lines) derived from velocity-encoded, cross-sectional, phase-contrast MRI. E, PA area of Subject B. CMR cross-sectional cine-loop image of the main PA in systole in Subject B. In normoxia on the left and hypoxia on the right. Figure was created with Microsoft Office (Microsoft, Redmond, WA), CVI42 (Circle Cardiovascular Imaging Inc, Calgary, AB, Canada), and EchoPac (General Electric, Boston, MA).We obtained data 1 month before, during, and 1, 3, 6, and 12 months after hypoxia, including velocity-encoded single-plane phase-contrast magnetic resonance imaging (3-T Siemens mBiograph positron emission tomography–magnetic resonance) of the pulmonary artery. Hypoxia was maintained by breathing equivalent hypoxic gas mixtures through a face mask during transfer to the scanner. We assessed right ventricular function and pulmonary artery pressure, area, flow, and distensibility by transthoracic echocardiography (LogiQ-S8, M5S-D sector probe, General Electric).Both subjects experienced high-altitude sickness symptoms. Neither developed overt high-altitude pulmonary edema or other serious adverse events. Hypoxia decreased arterial partial pressure of oxygen to a minimum of 36 mm Hg in Subject A and 33 mm Hg in Subject B. In both, pulmonary pressure increased during hypoxia, albeit to different extents (Figure [B]). Right ventricular to atrial maximum systolic pressure gradient (RVAsPG) was related to decreases in oxygen concentration in both subjects (Subject A: r=0.949, P<0.001; Subject B: r=0.989, P<0.001). In Subject A, RVAsPG was 17 mm Hg before and increased to a maximum of 44 mm Hg during hypoxia. RVAsPG remained stably elevated during hypoxia. In Subject B, RVAsPG was 19 mm Hg at baseline, peaked at 66 mm Hg in 8.5% oxygen, and declined to 44 mm Hg despite maintained hypoxia. RVAsPG was still closely correlated with decrease in oxygen in both subjects when normalized to cardiac output, derived from biventricular volumetry and aortic and pulmonary artery flow. End-systolic eccentricity index increased with hypoxia (D-shaped left ventricle, Figure [C]). Although we observed evidence of pericardial constraint (fluttering interventricular septum/septal bounce), right ventricular function measured by tricuspid annulus systolic excursion, fractional area change, and lateral tricuspid tissue velocity was preserved. Troponin T and BNP (B-type natriuretic peptide) were never elevated.With hypoxia, pulmonary artery area increased 1.5 cm2 (20%) in Subject A and 3.5 cm2 (44%) in Subject B (Figure [D and E]). Pulmonary artery distensibility decreased with hypoxia to 0.51%/mm Hg (baseline, 1.48%/mm Hg) in Subject A and 0.77%/mm Hg (baseline, 2.87%/mm Hg) in Subject B. In both, distensibility was correlated with oxygen levels (Subject A: r=0.799, P=0.017; Subject B: r=0.961, P<0.001) and RVAsPG (Subject A: r=−0.847, P=0.08, Subject B: r=−0.980, P<0.001; Figure [D]). All these changes resolved in normoxia within 36 hours for echocardiographic findings and 30 days for magnetic resonance imaging measurements. Throughout the study (days 1–35, Figure [A]), linear mixed-effect model analysis showed that Subject A compared with Subject B had lower heart rate (Δ=8.2 bpm, P<0.001), higher systolic and diastolic blood pressures (Δ=7.5 mm Hg, P<0.001; Δ=16.5 mm Hg, p<0.001), higher saturation (Δ=9.6%, P<0.001), and a higher respiratory minute volume (Δ=7.4 L/min, P<0.001). The analysis included 32 data points. The Kolmogorov-Smirnov test indicated normal distribution for all data.Severe pulmonary hypertension during several weeks of sustained normobaric hypoxia was well tolerated without progression to cardiac decompensation. Strikingly, pulmonary hypertension regressed in 1 subject despite sustained hypoxia. This finding suggests the possibility of tachyphylaxis of the pulmonary vascular response to severe hypoxia. Pulmonary pressure is affected by hypoxic vasoconstriction, inflammation, and vascular remodeling. Vascular remodeling may be initiated within 8 hours of hypoxia.2,5 The rapid reversal of functional and morphological changes in the pulmonary circulation is unexpected and challenges current concepts concerning the pathogenesis of hypoxia-induced pulmonary hypertension. Moreover, our findings may have implications for high-altitude medicine and pave the way for studies translating the finding that hypoxia promotes cardiac regeneration from mice to human beings.AcknowledgmentsThe authors thank Peter Hackett for his clinical perception and opinion while conducting the study.Sources of FundingThis work was supported by programmatic funding of the German Aerospace Center. Dr Hoffmann received funding by the German Aerospace Center (50WB1517) and the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, 50WB1816).DisclosuresNone.Footnotes*Drs Hoffmann and Limper contributed equally.https://www.ahajournals.org/journal/circThe data supporting the results are available from the corresponding author on reasonable request.Guest Editor was Suzanne Oparil, MD.Fabian Hoffmann, MD, Department of Cardiovascular Aerospace Medicine, German Aeropsace Center, Linder Hoehe, 51147 Cologne, Germany. Email fabian.[email protected]de or fabian.[email protected]deReferences1. Savla JJ, Levine BD, Sadek HA. The effect of hypoxia on cardiovascular disease: friend or foe?High Alt Med Biol. 2018; 19:124–130. doi: 10.1089/ham.2018.0044CrossrefMedlineGoogle Scholar2. Swenson ER. Hypoxic pulmonary vasoconstriction.High Alt Med Biol. 2013; 14:101–110. doi: 10.1089/ham.2013.1010CrossrefMedlineGoogle Scholar3. Groves BM, Reeves JT, Sutton JR, Wagner PD, Cymerman A, Malconian MK, Rock PB, Young PM, Houston CS. Operation Everest II: elevated high-altitude pulmonary resistance unresponsive to oxygen.J Appl Physiol (1985). 1987; 63:521–530. doi: 10.1152/jappl.1987.63.2.521CrossrefMedlineGoogle Scholar4. Nakada Y, Canseco DC, Thet S, Abdisalaam S, Asaithamby A, Santos CX, Shah AM, Zhang H, Faber JE, Kinter MT, et al. Hypoxia induces heart regeneration in adult mice.Nature. 2017; 541:222–227. doi: 10.1038/nature20173CrossrefMedlineGoogle Scholar5. Dorrington KL, Clar C, Young JD, Jonas M, Tansley JG, Robbins PA. Time course of the human pulmonary vascular response to 8 hours of isocapnic hypoxia.Am J Physiol. 1997; 273(pt 2):H1126–H1134. doi: 10.1152/ajpheart.1997.273.3.H1126MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Limper U, Hoffmann F, Zaha V, Reuter H, Hein M, Sadek H, Levine B, Jordan J and Tank J (2021) Disconnect between hypoxaemia and dyspnoea in severe sustained hypoxia, European Journal of Anaesthesiology, 10.1097/EJA.0000000000001478, 38:7, (798-800), Online publication date: 1-Jul-2021. Limper U (2020) Difficult physiology of airway management: mind the interaction between hypoxia types, British Journal of Anaesthesia, 10.1016/j.bja.2020.07.041, 125:5, (e415-e416), Online publication date: 1-Nov-2020. May 5, 2020Vol 141, Issue 18 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.045192PMID: 32364773 Originally publishedMay 4, 2020 Keywordshypertension, pulmonaryhypoxiahemodynamicsPDF download Advertisement SubjectsHemodynamicsPhysiologyPulmonary HypertensionTranslational Studies