Autonomic Cardiovascular Responses in Acclimatized Lowlanders on Prolonged Stay at High Altitude: A Longitudinal Follow Up Study

Acute exposure to hypobaric hypoxia at high altitude is reported to cause sympathetic dominance that may contribute to the pathophysiology of high altitude illnesses. The effect of prolonged stay at high altitude on autonomic functions, however, remains to be explored. Thus, the present study aimed at investigating the effect of high altitude on autonomic neural control of cardiovascular responses by monitoring heart rate variability (HRV) during chronic hypobaric hypoxia. Baseline electrocardiography (ECG) data was acquired from the volunteers at mean sea level (MSL) (<250 m) in Rajasthan. Following induction of the study population to high altitude (4500–4800 m) in Ladakh region, ECG data was acquired from the volunteers after 6 months (ALL 6) and 18 months of induction (ALL 18). Out of 159 volunteers who underwent complete investigation during acquisition of baseline data, we have only included the data of 104 volunteers who constantly stayed at high altitude for 18 months to complete the final follow up after 18 months. HRV parameters, physiological indices and biochemical changes in serum were investigated. Our results show sympathetic hyperactivation along with compromise in parasympathetic activity in ALL 6 and ALL 18 when compared to baseline data. Reduction of sympathetic activity and increased parasympathetic response was however observed in ALL 18 when compared to ALL 6. Our findings suggest that autonomic response is regulated by two distinct mechanisms in the ALL 6 and ALL 18. While the autonomic alterations in the ALL 6 group could be attributed to increased sympathetic activity resulting from increased plasma catecholamine concentration, the sympathetic activity in ALL 18 group is associated with increased concentration of serum coronary risk factors and elevated homocysteine. These findings have important clinical implications in assessment of susceptibility to cardio-vascular risks in acclimatized lowlanders staying for prolonged duration at high altitude.

[1]  S. Niermeyer Cardiopulmonary transition in the high altitude infant. , 2003, High altitude medicine & biology.

[2]  A. Delabays,et al.  Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema. , 1999, Circulation.

[3]  L. Bernardi Heart Rate and Cardiovascular Variability at High Altitude , 2007, 2007 29th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[4]  H Kenneth Walker,et al.  Clinical methods: The history, physical, and laboratory examinations , 1976 .

[5]  J. Eastman,et al.  Ultramicro determination of serum triglycerides by bioluminescent assay. , 1981, Clinical chemistry.

[6]  R Clarke,et al.  Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. , 1998, Archives of neurology.

[7]  J. Michael Textbook of Medical Physiology , 2005 .

[8]  J. Windsor,et al.  A review of electrocardiography in the high altitude environment. , 2010, High altitude medicine & biology.

[9]  P. Wood,et al.  National Cholesterol Education Program recommendations for measurement of high-density lipoprotein cholesterol: executive summary. The National Cholesterol Education Program Working Group on Lipoprotein Measurement. , 1995, Clinical chemistry.

[10]  F. Lin,et al.  Effect of Rapid Ascent to High Altitude on Autonomic Cardiovascular Modulation , 2008, The American journal of the medical sciences.

[11]  J. Richalet,et al.  Changes in plasma lipids and lipoprotein cholesterol during a high altitude mountaineering expedition (4800 m) , 2004, European Journal of Applied Physiology and Occupational Physiology.

[12]  K. Felmingham,et al.  Depression, Comorbid Anxiety Disorders, and Heart Rate Variability in Physically Healthy, Unmedicated Patients: Implications for Cardiovascular Risk , 2012, PloS one.

[13]  L E Banderet,et al.  Elevation-dependent symptom, mood, and performance changes produced by exposure to hypobaric hypoxia. , 1998, The International journal of aviation psychology.

[14]  H. Shimada,et al.  Alterations in autonomic nervous control of heart rate among tourists at 2700 and 3700 m above sea level , 2001, Wilderness & environmental medicine.

[15]  James Milledge,et al.  High altitude medicine and physiology , 1989 .

[16]  D. Böning,et al.  Changes of hematocrit and hemoglobin concentration in the cold Himalayan environment in dependence on total body fluid , 2010, Sleep and Breathing.

[17]  Fred Macsorley High altitude medicine and physiology. , 2001 .

[18]  J. Guenette,et al.  Oximetry, heart rate variability, and the diagnosis of mild-to-moderate acute mountain sickness , 2010, European journal of emergency medicine : official journal of the European Society for Emergency Medicine.

[19]  Armelle Prunier,et al.  Heart rate variability as a measure of autonomic regulation of cardiac activity for assessing stress and welfare in farm animals — A review , 2007, Physiology & Behavior.

[20]  J. Manson,et al.  Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. , 2008, JAMA.

[21]  T. Kuo,et al.  Alternations of Heart Rate Variability at Lower Altitude in the Predication of Trekkers With Acute Mountain Sickness at High Altitude , 2010, Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine.

[22]  J. Skatrud,et al.  Exposure to hypoxia produces long-lasting sympathetic activation in humans. , 2001, Journal of applied physiology.

[23]  A. León,et al.  High density lipoprotein cholesterol increases with living altitude. , 2000, International journal of epidemiology.

[24]  M. Zaccaria,et al.  Cardiovascular neural regulation during and after prolonged high altitude exposure. , 1994, European heart journal.

[25]  Natalia M. Arzeno,et al.  Chaotic Signatures of Heart Rate Variability and Its Power Spectrum in Health, Aging and Heart Failure , 2009, PloS one.

[26]  A Calciati,et al.  Cardiovascular autonomic modulation and activity of carotid baroreceptors at altitude. , 1998, Clinical science.

[27]  A. Wright,et al.  Systemic Blood Pressure, Arterial Stiffness and Pulse Waveform Analysis at Altitude , 2011, Journal of the Royal Army Medical Corps.

[28]  M. Muntzel,et al.  Acute homocysteine administration does not elevate sympathetic nerve activity in rats. , 2006, Atherosclerosis.

[29]  J. Weil Sleep at high altitude. , 2004, High altitude medicine & biology.

[30]  J. Brugniaux,et al.  Effects of intermittent hypoxia on heart rate variability during rest and exercise. , 2005, High altitude medicine & biology.

[31]  J. Machan,et al.  Physiologic affects of altitude on recreational climbers. , 2009, American Journal of Emergency Medicine.

[32]  K. Cianflone,et al.  Plasma adipokine and hormone changes in mountaineers on ascent to 5300 meters. , 2011, Wilderness & environmental medicine.

[33]  J. Barthélémy,et al.  Cardiac baroreflex control in humans during and immediately after brief exposure to simulated high altitude , 2002, Clinical physiology and functional imaging.

[34]  R. Hughson,et al.  Sympathetic and parasympathetic indicators of heart rate control at altitude studied by spectral analysis. , 1994, Journal of applied physiology.

[35]  A. Beck,et al.  An inventory for measuring depression. , 1961, Archives of general psychiatry.

[36]  P. Bachorik,et al.  National Cholesterol Education Program recommendations for measurement of low-density lipoprotein cholesterol: executive summary. The National Cholesterol Education Program Working Group on Lipoprotein Measurement. , 1995, Clinical chemistry.

[37]  H. Knapp,et al.  Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. , 1999, Circulation.

[38]  L. Pugh Man at high altitude: studies carried out in the Himalaya. , 1964, The Scientific basis of medicine annual reviews.

[39]  U. Rajendra Acharya,et al.  Heart rate variability: a review , 2006, Medical and Biological Engineering and Computing.

[40]  P. Paulev,et al.  Altitude adaptation through hematocrit changes. , 2007, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[41]  P. Ueland,et al.  Total homocysteine in plasma or serum: methods and clinical applications. , 1993, Clinical chemistry.

[42]  R. Perini,et al.  Effects of high altitude acclimatization on heart rate variability in resting humans , 2004, European Journal of Applied Physiology and Occupational Physiology.

[43]  A. Kazory Emergence of blood urea nitrogen as a biomarker of neurohormonal activation in heart failure. , 2010, The American journal of cardiology.

[44]  N. Ayas,et al.  Long‐term intermittent hypoxia increases sympathetic activity and chemosensitivity during acute hypoxia in humans , 2006, The Journal of physiology.

[45]  J. Temte,et al.  Elevation of serum cholesterol at high altitude and its relationship to hematocrit. , 1996, Wilderness & environmental medicine.

[46]  B. Groves,et al.  Arterial catecholamine responses during exercise with acute and chronic high-altitude exposure. , 1991, The American journal of physiology.

[47]  J. Calbet Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans , 2003, The Journal of physiology.

[48]  M. Sander,et al.  Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia , 2003, The Journal of physiology.

[49]  K. Bloch,et al.  Higher pulmonary artery pressure in children than in adults upon fast ascent to high altitude , 2008, European Respiratory Journal.

[50]  Henny H. Billett,et al.  hemoglobin and hematocrit , 2022 .

[51]  L. B. Foster,et al.  A single-reagent manual method for directly determining urea nitrogen in serum. , 1971, Clinical chemistry.

[52]  B. Morrissey,et al.  Upregulation of nitric oxide synthase in mice with severe hypoxia-induced pulmonary hypertension , 2001, Respiratory research.

[53]  E. Wong,et al.  Kinetic serum creatinine assays. II. A critical evaluation and review. , 1980, Clinical chemistry.

[54]  G. Mazzuero,et al.  Autonomic cardiovascular regulation in subjects with acute mountain sickness. , 2005, American journal of physiology. Heart and circulatory physiology.

[55]  U. Boutellier,et al.  Effects of atropine and propranolol on the respiratory, circulatory, and ECG responses to high altitude in man , 2004, European Journal of Applied Physiology and Occupational Physiology.

[56]  D. Cardinali,et al.  Heart Rate Nonlinear Dynamics During Sudden Hypoxia at 8230 m Simulated Altitude , 2010, Wilderness & environmental medicine.

[57]  J. J. de la Cruz,et al.  Chronic intermittent hypoxia at high altitude exposure for over 12 years: assessment of hematological, cardiovascular, and renal effects. , 2007, High altitude medicine & biology.

[58]  H. Gunga,et al.  Austrian Moderate Altitude Study 2000 (AMAS 2000). The effects of moderate altitude (1,700 m) on cardiovascular and metabolic variables in patients with metabolic syndrome , 2003, European Journal of Applied Physiology.

[59]  P. Wagner,et al.  β‐Adrenergic or parasympathetic inhibition, heart rate and cardiac output during normoxic and acute hypoxic exercise in humans , 2003, The Journal of physiology.

[60]  W. Kraft,et al.  [Alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), alkaline phosphatase (AP) and gamma-glutamyltransferase (GGP) in intestinal diseases of dogs]. , 1995, Berliner und Munchener tierarztliche Wochenschrift.

[61]  H. Shimada,et al.  Rate pressure product and oxygen saturation in tourists at approximately 3000 m above sea level , 1998, International archives of occupational and environmental health.

[62]  Günter Edlinger,et al.  EEG, ECG and oxygen concentration changes from sea level to a simulated altitude of 4000m and back to sea level , 2008, Neuroscience Letters.

[63]  P. Fu,et al.  Enzymatic determination of total serum cholesterol. , 1974, Clinical chemistry.

[64]  H. McNulty,et al.  B-vitamins, homocysteine metabolism and CVD , 2004, Proceedings of the Nutrition Society.

[65]  D. Vearrier,et al.  Occupational health of miners at altitude: Adverse health effects, toxic exposures, pre-placement screening, acclimatization, and worker surveillance , 2011, Clinical toxicology.

[66]  Michael S. Bahrke,et al.  Effects of Altitude on Mood, Behaviour and Cognitive Functioning , 1993, Sports medicine.

[67]  A. Louhija Hypertriglyceridemia in rats at simulated high altitudes , 1969, Experientia.

[68]  C. Glueck,et al.  Lipids and lipoproteins in subjects at 1,000 and 3,500 meter altitudes. , 1979, Archives of environmental health.

[69]  C. Beall Oxygen saturation increases during childhood and decreases during adulthood among high altitude native Tibetians residing at 3,800-4,200m. , 2000, High altitude medicine & biology.

[70]  O. Appenzeller,et al.  Autonomic regulation of heart rate and peripheral circulation: comparison of high altitude and sea level residents. , 1996, Clinical science.

[71]  X. Liu,et al.  [Analysis of heart rate variability during acute exposure to hypoxia]. , 2001, Hang tian yi xue yu yi xue gong cheng = Space medicine & medical engineering.

[72]  D. Roberts,et al.  Oxidative stress in humans during work at moderate altitude. , 1999, The Journal of nutrition.

[73]  G. B. Moody,et al.  Heart rate and respiratory rhythm dynamics on ascent to high altitude. , 1995, British heart journal.

[74]  G. Boss,et al.  Reactions of nitric oxide with vitamin B12 and its precursor, cobinamide. , 2003, Biochemistry.

[75]  Olaf Stanger,et al.  Interactions of Homocysteine, Nitric Oxide, Folate and Radicals in the Progressively Damaged Endothelium , 2003, Clinical chemistry and laboratory medicine.

[76]  B. Kayser,et al.  Controversies in altitude medicine. , 2005, Travel medicine and infectious disease.

[77]  S. Malpas Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. , 2010, Physiological Reviews.

[78]  S. Cerutti,et al.  Autonomic function and baroreflex sensitivity during angiotensin-converting enzyme inhibition or angiotensin II AT-1 receptor blockade in essential hypertensive patients , 2001, Acta cardiologica.

[79]  Mika P. Tarvainen,et al.  Software for advanced HRV analysis , 2004, Comput. Methods Programs Biomed..

[80]  Luiz Carlos Marques Vanderlei,et al.  Basic notions of heart rate variability and its clinical applicability. , 2009, Revista brasileira de cirurgia cardiovascular : orgao oficial da Sociedade Brasileira de Cirurgia Cardiovascular.

[81]  K. Yoshinaga,et al.  Higher Plasma Homocysteine Concentration Is Associated with More Advanced Systemic Arterial Stiffness and Greater Blood Pressure Response to Stress in Hypertensive Patients , 2006, Hypertension Research.

[82]  W Selvamurthy,et al.  Responses of the autonomic nervous system during acclimatization tp high altitude in man. , 1976, Aviation, space, and environmental medicine.

[83]  A. Aubert,et al.  Heart Rate Variability in Athletes , 2003, Sports medicine.

[84]  R. Singh,et al.  Determinants of Acclimatisation in High Altitude. , 2010, Medical journal, Armed Forces India.

[85]  J. Weil,et al.  Autonomic Cardiovascular Control during Hypoxia in the Dog , 1979, Circulation research.

[86]  C. Held,et al.  Prognostic implications of autonomic function assessed by analyses of catecholamines and heart rate variability in stable angina pectoris , 2002, Heart.

[87]  P. Robach,et al.  Autonomic control of the cardiovascular system during acclimatization to high altitude: effects of sildenafil. , 2004, Journal of applied physiology.

[88]  Juan F. Ramirez-Villegas,et al.  Heart Rate Variability Dynamics for the Prognosis of Cardiovascular Risk , 2011, PloS one.

[89]  L. Hartley,et al.  Reduction of maximal exercise heart rate at altitude and its reversal with atropine. , 1974, Journal of applied physiology.

[90]  P. K. Banerjee,et al.  Effect of simulated ascent to 3500 meter on neuro-endocrine functions. , 2006, Indian journal of physiology and pharmacology.

[91]  P. Lazzerini,et al.  Homocysteine and P wave dispersion in patients with heart transplantation , 2011, Clinical transplantation.

[92]  K Zuzewicz,et al.  Heart rate variability in exposure to high altitude hypoxia of short duration. , 1999, International journal of occupational safety and ergonomics : JOSE.

[93]  A. Krag,et al.  Reduced baroreflex sensitivity and pulmonary dysfunction in alcoholic cirrhosis: effect of hyperoxia. , 2010, American journal of physiology. Gastrointestinal and liver physiology.

[94]  J. Griffin,et al.  Textbook of Medical Physiology 4th Ed , 1971 .

[95]  Charles S. Houston,et al.  THE LAKE-LOUISE ACUTE MOUNTAIN-SICKNESS SCORING SYSTEM , 1993 .

[96]  C. Beall,et al.  Nitric oxide in adaptation to altitude. , 2012, Free radical biology & medicine.

[97]  O. Appenzeller,et al.  Respiratory and cardiovascular adaptations to progressive hypoxia; effect of interval hypoxic training. , 2001, European heart journal.

[98]  Pugh Lg Man at high altitude: studies carried out in the Himalaya. , 1964 .

[99]  James T. Wu Circulating Homocysteine is an Inflammation Marker and a Risk Factor of Life-Threatening Inflammatory Diseases , 2007 .

[100]  T. Betts,et al.  High Altitude Arrhythmias , 2008, Cardiology.

[101]  M. Rostrup Catecholamines, hypoxia and high altitude. , 1998, Acta physiologica Scandinavica.

[102]  Walker Hk,et al.  Hemoglobin and Hematocrit -- Clinical Methods: The History, Physical, and Laboratory Examinations , 1990 .

[103]  F. Léon-Velarde,et al.  Blood pressure responses in young adults first exposed to high altitude for 12 months at 3550 m. , 2009, High altitude medicine & biology.

[104]  C. Beall Adaptations to Altitude: A Current Assessment , 2001 .

[105]  P. K. Banerjee,et al.  Body composition & cardiovascular functions in healthy males acclimatized to desert & high altitude. , 2009, The Indian journal of medical research.

[106]  P. Paulev,et al.  Do Over 200 Million Healthy Altitude Residents Really Suffer from Chronic Acid–Base Disorders? , 2010, Indian Journal of Clinical Biochemistry.

[107]  A. Smit,et al.  Reduced autonomic activity during stepwise exposure to high altitude. , 2001, Acta physiologica Scandinavica.

[108]  P. Ueland,et al.  Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. , 1989, The Journal of laboratory and clinical medicine.

[109]  B. Mcwilliams,et al.  Pulmonary ventilatory function decreases in proportion to increasing altitude. , 1997, Wilderness & environmental medicine.

[110]  D. Peñaloza,et al.  Pulmonary hemodynamics in children living at high altitudes. , 2008, High altitude medicine & biology.

[111]  R. Hainsworth,et al.  The autonomic nervous system at high altitude , 2007, Clinical Autonomic Research.

[112]  R. Naeije Physiological adaptation of the cardiovascular system to high altitude. , 2010, Progress in cardiovascular diseases.

[113]  P. Cerretelli,et al.  Autonomic nervous control of heart rate at altitude (5050 m) , 2004, European Journal of Applied Physiology and Occupational Physiology.