Scientific Article Increased Cardiometabolic Risk and

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Therefore, high-altitude research could version of WHO S1EPS approach questionnaire for ...... Wilson PW; D'Agostino RB, Parise H, Sullivan L, and Meigs lB.

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HIGH ALTITUDE MEDICINE & BIOLOGY Volume 17, Number 2,2016 © Mary Ann Liebert, Inc. 001: 10.1089/ham.2015.0084

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Scientific Article

Increased Cardiometabolic Risk and Worsening Hypoxemia at High Altitude Catherine H. Miele,1 Alan R. Schwartz, 1 Robert H. Gilman, 2 Luu Pham, 1 Robert A. Wise, 1 Victor G. Davila-Roman,3 Jonathan C. Jun,1 Vsevolod Y. Polotsky,1 J. Jaime Miranda,4,5 Fabiola Leon-Velarde,5 and William Checkley1,2


Miele, Catherine H., Alan R. Schwartz, Robert H. Gilman, Luu Pham, Robert A. Wise, Victor G. Davila-Roman, Jonathan C. Jun, Vsevolod Y. Polotsky, J. Jaime Miranda, Fabiola Leon-Velarde, and William Checldey. Increased cardiometabolic risk and worsening hypoxemia at high altitude. High Alt Med Bioi. 00:000-000, 2016Metabolic syndrome, insulin resistan~, diabetes, and dyslipidemia are associated with an increased risk of cardiovascular disease. While excessive erythrocytosis is associated with cardiovascular complications, it is unclear how worsening hypoxemia of any degree affects cardiometabolic risk factors in high-altitude populations. We studied the relationship between daytime resting oxyhemoglobin saturation and cardiometabolic risk factors in adult participants living in Puno, Peru (3825 m above sea level). We used multivarlable logistic regression models to study the relationship between having a lower oxyhemoglobin saturation and markers of cardiometabolic risk. Nine hundred and fifty-four participants (mean age 55 years, 52% male) had information available on pulse oximetry and markers of cardiometabolic risk. Average oxyhemoglobin saturation was 90% (interquartile range 880/0-92%) and 43 (4.5%) had excessive erythrocytosis. Older age, decreased height-adjusted lung function, and higher body mass index (BMI) were associated with having an oxyhemoglobin saturation ~85%. When adjusting for age, sex, socioeconomic status, having excessive erythrocytosis, and site, we found that each 5% decrease in oxyhemoglobin saturation was associated with a higher adjusted odds of metabolic syndrome (OR = 1.35,95% CI: 1.07-1.72, p2 mass units (OR = 1.29, 95% CI: 1.00-1.67, p3mgIL (OR= 1.46,95% CI: 1.09-1.96, p < 0.01). In high-altitude populations in Puno, Peru, a higher BMI and lower pulmonary function were associated with lower resting daytime oxyhemoglobin saturation. Lower resting oxyhemoglobin saturation, in turn, was associated with higher odds of having mUltiple unfavorable cardiometabolic factors. Worsening hypoxia of any degree in high-altitude dwellers may be an independent risk factor for cardiovascular disease. Key Words: altitude; diabetes; hypoxemia; insulin resistance; metabolic syndrome

cluding abdominal obesity (as a proxy for body mass index [BMI]), atherogenic dyslipidemia, hypertension, and insulin resistance, all of which have been associated with increased risk of cardiovascular disease and death (Grundy et aI., 2004; Wilson et aI., 2005). Population-based studies have found that severe pUlmonary disease and obstructive sleep apnea are also associated with increased cardiovascular disease



the leading cause of death worldwide (Despres et aI., 2008; Mottillo et aI., 2010) and is responsible for 18 million deaths each year (World Health Organization, 2015). Metabolic syndrome represents a cluster of cardiovascular and metabolic risk factors, inARDIOVASCULAR DISEASE IS

lDivision of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, Maryland. 2Program in Global Disease Epidemiology and Control, Department of International Health, Bloomberg School of Public Health, Johns HOf.kins University, Baltimore, Maryland. Division of Cardiology, Department of Medicine, Washington University, St. Louis, Missouri. 4CRONICAS Center of Excellence for Chronic Diseases, Universidad Peruana Cayetano Heredia, Lima, Peru. 5Departamento de Medicina, Escuela de Medicina, Universidad Peruana Cayetano Heredia, Lima, Peru.




morbidity and mortality (Kannel et aI., 1983; Schroeder et al., Study participants 2003). Since both pulmonary disease and sleep apnea lead to We identified a sex- and age-stratified random sample of hypoxemia, it has been hypothesized that hypoxemia is re- adults aged ~35 years. We aimed to enroll 1000 subjects in sponsible for detrimental cardiovascular outcomes. Puno and stratified recruitment to include ,...., 500 participants High altitude provides a natural laboratory to study the as- each from the urban and rural settings (Miranda et aI., 2012). sociation between worsening hypoxemia and cardiometabolic We recorded oxyhemoglobin saturations during baseline risk. The partial pressure of oxygen at high altitudes (>2500 m evaluation in 95% of participants (489 urban and 465 rural above sea level) is reduced when compared to that at sea level, participants). Exclusion criteria were pregnancy, inability to resulting in chronic hypoxemia of varying degrees in high- participate in questionnaires or spirometer due to physical landers. In some, hypoxemia may be exaggerated and lead to disability, and active pulmonary tuberculosis. Fieldworkers the development of chronic mountain sickness, a prevalent obtained verbal consent from study participants before encondition in the Peruvian Andes that leads to cardiovascular rollment. The study was approved by the Institutional Review decompensation, stroke, and heart failure (Monge, 1942; Boards at Universidad Peruana Cayetano Heredia and A.B. Whayne, 2004; LeOn-Velarde et al., 2005; Vargas and Spiel- PRlSMA in Lima, Peru, and the Johns Hopkins Bloomberg vogel, 2006). School of Public Health in Baltimore. There is conflicting evidence that high-altitude dwellers may have either increased (Baracco et aI., 2007; Malaga et al., 20 10) or decreased odds of having metabolic syndrome (Woo1cott Data collection et al., 2014) when compared with sea-level counterparts. Trained technicians measured weight, height, and blood Laboratory studies have demonstrated that intermittent hyp- pressure. Data collected include several factors potentially oxemia leads to insulin resistance (Polotsky et aI., 2004) and associated with chronic disease, such as age, sex, years of low-grade systemic inflammation (Ryan et al., 2005), likely education, occupation, demographic information, other sociocontributing to the development of cardiovascular disease; economic variables, smoking habits, biomass fuel use, and selfhowever, a better understanding of underlying-mechanisms of reported medical conditions and self-reported family medical hypoxemia-associated cardiometabolic disease risk is lacking. conditions (Miranda et al., 2012). All interviews were conCurrent evidence has focused on the role of intermittent hyp- ducted in Spanish, Aymara, or Quechua according to the paroxemia on cardiometabolic disease and not on the role of. ticipant's primary language of preference. We used a modified chronic hypoxemia. Therefore, high-altitude research could version of WHO S1EPS approach questionnaire for surveilprovide relevant epidemiological data to more clearly elicit the lance of noncommunicable disease (World Health Organizalink between chronic hypoxemia and cardiometabolic risk. tion, 2014). Pulse oximetry was measured using a handheld In a prior study, we found that excessive erythrocytosis, the device (Rad-5v, Masimo, Irvine, CA) while participants were hallmark of Chronic Mountain Sickness, was associated with awake, upright, and resting comfortably (Luks and Swenson, higher odds of having metabolic syndrome (De Ferrari et aI., 2011). Oxyhemoglobin saturation was recorded after the 2014). The overall prevalence of excessive erythrocytosis was reading stabilized for more than 10 seconds. The Rad-5v has an 4.5%, but our earlier analyses did not explore the relationship oxyhemoglobin saturation accuracy range of 70%-100% with between oxyhemoglobin saturation of varying degrees and ±3%. Fasting blood samples were obtained and analyzed in a cardiometabolic risk profiles. We hypothesize that worsening single facility using a standardized approach. Hemoglobin was hypoxemia of any degree, even before the development of determined by the automated sodium lauryl sulfate method for excessive erythrocytosis or Chronic Mountain Sickness, con- the detection of methemoglobin. All tests were processed in a tributes to increased cardiometabolic risk and thus it may be a centralized testing facility (Miranda et al., 2012). Plasma marker of increased cardiometabolic disease risk. glucose was measured using an enzymatic colorimetric method (GOD-PAP; Modular P-ElRoche-Cobas). Trained technicians Methods measured pre- and post-bronchodilator spirometry with the Easy-On-PC spirometer (ndd Medizintechnik AG) following Setting and design standard guidelines (Miller et al., 2005). . We leveraged data from an existing cohort of adult participants living at high altitude to evaluate the relationship Definitions between degree of hypoxemia and cardiometabolic risk. The We defined oxyhemoglobin saturation as low if pulse CRONICAS study is a longitudinal, population-based study aimed to determine the prevalence and risk factors for oximetry reading was ::;;85% and acceptable if >85%; exchronic pulmonary and cardiovascular disease across four cessive erythrocytosis as having a hemoglobin ~21 gldL in disparate regions in Peru. The study protocol has been de- men and ~19 gldL in women (LeOn-Velarde et aI., 2005); and scribed in detail elsewhere (Miranda et aI., 2012). Data for metabolic syndrome. following the 2009 harmonized definiour study were taken from the high-altitude population in tion that incorporated the following region-specific cutoffs Puno, Peru. Puno is a southwestern city in the Andes, located (Alberti et aI., 2009): elevated waist circumference (~90cm on the shores of Lake Titicaca at 3825 m above sea level. A in men and ~80 in cm women); elevated triglycerides large proportion of participants were of Aymara and Quechua (~150 mg/dL) or drug treatment; reduced high-density liethnicity, the second and third largest ethnic group in Peru . poprotein (HDL)-cholesterol «40mg/dL in males and after mestizos (i.e., mixed Amerindian and European ances-

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