The Effect of Hypoxia on Cardiovascular Disease: Friend or Foe?

Abstract

Savla, Jainy J., Benjamin D. Levine, and Hesham A. Sadek. The effect of hypoxia on cardiovascular disease: Friend or foe? High Alt Med Biol. 19:124–130, 2018.—Over 140 million people reside at altitudes exceeding 2500 m across the world, resulting in exposure to atmospheric (hypobaric) hypoxia. Whether this chronic exposure is beneficial or detrimental to the cardiovascular system, however, is uncertain. On one hand, multiple studies have suggested a protective effect of living at moderate and high altitudes for cardiovascular risk factors and cardiovascular disease (CVD) events. Conversely, residence at high altitude comes at the tradeoff of developing diseases such as chronic mountain sickness and high-altitude pulmonary hypertension and worsens outcomes for diseases such as chronic obstructive pulmonary disease. Interestingly, recently published data show a potential role for severe hypoxia as a unique and unexpected therapy after myocardial infarction. In this review, we will discuss the current literature evaluating the effects of altitude exposure and the accompanying hypoxia on health and the potential therapeutic applications of hypoxia on CVD.

Across the world, many diverse populations have been residing at altitudes exceeding 2500 m for hundreds and in some regions, perhaps thousands of years (Moore et al., 1998). Despite this long history, the effects of moderate- and high-altitude exposure on human health remain uncertain. Numerous epidemiologic, physiologic, and animal studies have been published evaluating the positive and negative effects of altitude on cardiovascular disease (CVD). Much of this published literature is conflicting on the specific role of altitude on the development of CVD or related conditions. Most importantly, the impact of exposure to atmospheric hypoxia, which accompanies living at altitude, is unclear and extremely difficult to isolate from the genetic and environmental factors that are well known to influence CVD among different populations. In this review, we will discuss the physiologic changes which occur with chronic altitude exposure, evaluate the current literature surrounding the positive and negative consequences of living at moderate altitude and examine the potential therapeutic applications of hypoxia. The cardiovascular response to altitude, both acute and chronic, has been reviewed recently in detail (Baggish et al., 2014; Levine, 2015) and thus will be covered only briefly in this study.

Cardiovascular Physiologic Changes After Altitude Exposure

With increases in altitude, there are decreases in barometric pressure. At moderate and high levels of altitude (Bartsch et al., 2008), this results in a reduction in the partial pressure of oxygen and ultimately leads to alveolar hypoxia. There are a number of well-defined changes that occur in the cardiovascular system after acute and chronic acclimatization to altitude. It should be noted that many of these studies were performed in healthy controls, the majority of which were healthy young men; thus, the data base regarding the effect of altitude on women, the elderly, or patients with systemic diseases is remarkably limited. With acute exposure, the stroke volume increases. After a few days, that initial increase abates and the stroke volume falls to levels that are lower than sea level (Richardson et al., 1967; Vogel et al., 1967; Hoon et al., 1977). Heart rate is also increased with altitude exposure and remains elevated with sustained exposure (Baggish et al., 2014; Siebenmann and Lundby, 2015). The degree of elevation in the heart rate correlates to the amount of elevation from sea level. Even with exposure to severe hypoxia, left ventricular contractility is preserved (Buch et al., 1980; Fowles and Hultgren, 1983; Reeves et al., 1987; Suarez et al., 1987). However, there are reductions in left ventricular end diastolic volume observed with sustained hypoxia. This finding is mostly attributed to a reduction in plasma volume, although pulmonary hypertension and ventricular function likely play some role depending on the degree of both absolute hypoxia and hypoxic pulmonary vasoconstriction (Alexander et al., 1967; Fowles and Hultgren, 1983; Suarez et al., 1987; Hirata et al., 1991). In addition, exercise capacity is reduced with exposure to altitude and the pulmonary artery pressure increases abruptly with exercise even after acclimatization. In terms of coronary blood flow, hypoxia results in increased levels of coronary blood flow to accommodate the reduction in arterial O₂ content, although ultimate values in the chronic state can vary between the right and left coronary arteries and depend on both the supply side (restoration of arterial oxygen content from acclimatization) and the demand side (myocardial oxygen demands based on HR and ventricular loading conditions) (Moret et al., 1972; Grover et al., 1976). Coronary flow reserve is preserved in healthy individuals at altitude, but decreases in those with known coronary artery disease (CAD) during exercise (Wyss et al., 2003; Arbab-Zadeh et al., 2009).

Multiple additional physiologic changes occur during sustained exposure to hypoxia that impact the cardiovascular system. Persistent exposure to altitude results in sympathetic hyperactivity (Hansen and Sander, 2003; Lundby et al., 2018), which leads to downregulation of beta receptors, the impact of which is unclear (Bristow et al., 1982; Kacimi et al., 1992). There are also changes in hemoglobin-O₂ affinity and hypoxia-mediated erythropoietin production, which stimulate red blood cell production. Although the red cell mass increases with time at altitude, the reduction in plasma volume that occurs with exposure to moderate and high altitudes persists resulting in a relative preservation of total blood volume (Myhre et al., 1970; Jain et al., 1980).

On a transcriptional level, many of these responses are mediated by the hypoxia-inducible factor (HIF) family of transcription factors binding to hypoxia-response elements located near genes that control these changes. The HIFs have been linked to a number of adaptive responses to hypoxia, including erythropoiesis (Semenza and Wang, 1992). In the Tibetan population, the role of variants in the HIF2α gene on adaptation to chronic hypoxia have been studied by a number of groups with links to lower hematocrit and lower pulmonary vasoconstriction response (Groves et al., 1993; Beall, 2000), although the influence of plasma volume regulation in this response has largely been ignored and may be important (Dunn et al., 2007). In addition to the HIF family, the expression patterns of over 40 genes are altered by hypoxia, including vascular endothelial-growth factor-a, pyruvate dehydrogenase kinase, isoform 1, inducible nitric oxide synthase, and prostaglandin I2 synthase. While some of these genes are known to work in specific pathways, the function of many of these genes is not known. In addition, genome wide association studies have identified variants in a number of genes that may facilitate adaptation to high altitude (Zimmerman et al., 1991; Semenza and Wang, 1992; Melillo et al., 1995; Tuder et al., 1995; Lau et al., 1997; Zaobornyj et al., 2009; Simonson et al., 2010; Hu et al., 2017). This may be of relevance especially in light of the known negative feed-back loop, which results in downregulation of HIF1α mRNA with prolonged hypoxia exposure (Ginouves et al., 2008).

With chronic exposure to altitude and hypoxia, there are moderate elevations in pulmonary artery pressure resulting from vascular remodeling. One of the key responses of vascular remodeling is muscularization of the distal vessels. The relationship between altitude and lung disease is further explored by Grissom and Jones in this issue. In terms of the systemic circulation, there are elevations in systemic arterial pressure and vascular resistance (Klausen, 1966; Vogel et al., 1967, 1974; Sharma et al., 1977; Bender et al., 1988; Wolfel et al., 1991, 1998; Savard et al., 1995). While these changes occur shortly after exposure to hypoxia, these changes do not seem to persist after several months (Marticorena et al., 1969; Sharma et al., 1978).

Is Residence at Altitude Beneficial?

The initial data evaluating the effects of altitude are derived from epidemiologic studies. While these studies compared high-altitude populations versus low-altitude populations, the published results are inconsistent across a variety of diseases. In terms of CVD, several studies show a reduced risk of CVD with increases in altitude, while multiple studies conclude the opposite result (Mortimer et al., 1977; Temte, 1996; al Tahan et al., 1998; Baibas et al., 2005; Al-Huthi et al., 2006). Similar conflicting findings are seen for studies evaluating risk factors for CVD such as hypertension and hyperlipidemia (de Mendoza et al., 1979; Mirrakhimov et al., 1985; Sharma, 1990; Khalid et al., 1994; Wolfel et al., 1994; al Tahan et al., 1998; Pasini et al., 1999; Dominguez Coello et al., 2000; Fiori et al., 2000; Jefferson et al., 2002). The majority of these conflicting findings result from confounding factors, which were not adequately addressed in the study design and analysis. In much of this literature, the comparison groups are heterogeneous in terms of ethnicity and traditional CVD risk factors. Additional factors that could affect assessment of the outcome such as access to healthcare, migration, exposure to relatively low altitudes and total altitude exposure over a lifetime were not assessed in many of these studies.

In 2009, Faeh et al. utilized the Swiss National Cohort Study Group to evaluate the effect of altitude on CVD. This study addresses many of the limitations of previous studies as the Swiss population is more homogenous and has access to universal healthcare, minimizing the role of healthcare utilization on CVD. In addition, this cohort has information on the location of birth and the place of residence to better estimate the amount of exposure to altitude. Using data from ∼1.64 million German Swiss residents, they show a beneficial effect of high altitude on CAD and stroke. Individuals who were born at high altitude also have an independent protective effect for CAD (Faeh et al., 2009).

The beneficial effects of high altitude on heart disease are consistently seen in other more recently published studies. Similar to Faeh et al. (2009) a study evaluating the US population examines the relationship between CVD and altitude. Using a variety of data sources, including the National Center for Health Statistics, the National Elevation Dataset, and the U.S. Census Estimates, they demonstrate a beneficial dose–response relationship between altitude and CVD. Their analysis adjusts for sociodemographic factors, migration, exposure to solar radiation, and cumulative exposure to smoking, addressing the weaknesses of previously published studies (Ezzati et al., 2012). A second study of heart disease in the United States from 2008 through 2011 uses data from 11 states considered to be low-altitude states and 5 states considered to be high-altitude states. Consistent with the recently published studies, they show that the incidence of heart diseases is lower in the high-altitude states (Hart, 2015). A follow-up study from the Swiss National Cohort evaluates the effects of environmental factors on cardiovascular mortality. Using data from 4.2 million individuals, they found that mortality from CVD decreases linearly with increases in altitude. While this association can be attributed to environmental factors such as low amounts of pollution or increased physical activity, the positive effect of altitude remains after adjusting for all other environmental factors (Faeh et al., 2016). Among dialysis patients, lower rates of myocardial infarction, stroke, and cardiovascular death are seen at higher altitudes (Winkelmayer et al., 2012).

The benefits of altitude exposure are described with several other diseases with close linkage to cardiovascular disorders. A cross sectional study from the United States shows that adults living at altitudes of 1500–3500 m are less likely to have diabetes and obesity compared with adults living at elevations of 0–499 m. After adjusting for factors such as age, physical activity, and obesity, the association between diabetes and altitude persisted (Woolcott et al., 2014). In terms of hyperlipidemia, a study of an Omani Arab population residing at high altitude demonstrates elevated high density lipoprotein cholesterol (HDL-C) levels, while a cross-sectional Turkish study shows that dyslipidemia is negatively associated with altitude (Bayram et al., 2014; Al Riyami et al., 2015). This effect is thought to be mediated through HIF1 in reducing cholesterol synthesis by 3-hydroxy-3-methylglutaryl-CoA reductase (Nguyen et al., 2007). However, these studies are limited by many of the confounders described above. The effect of altitude is also seen on obesity and metabolic syndrome. Among overweight service members in the U.S. Army and Air Force, those stationed at high-altitude locations have a lower incidence of obesity (Voss et al., 2014). In a comparison of high and low populations in Peru, individuals residing in high-altitude regions are less likely to have metabolic syndrome, elevated high-sensitivity C-reactive protein, and insulin resistance (Benziger et al., 2015). The interpretation of these studies is limited by the small sample size and presence of residual confounding. When looking at less common cardiac conditions, improved survival is seen in patients living above 2000 feet after heart transplant (Wozniak et al., 2012), while in a small series of patients undergoing surgical repair of atrial septal defects or ventricular septal defects, patients at high altitude have lower troponin I values and change in brain natriuretic peptide after surgery (Hu et al., 2014). While these studies highlight an interesting potential benefit to altitude exposure on postsurgical outcomes, these results must be interpreted with caution due to the small sample sizes and the limitations inherent to the datasets queried.

The Tradeoffs

The lower incidences of obesity, diabetes, hyperlipidemia, and CAD for populations that live at high altitudes come at a price. A well described possible consequence of chronic altitude exposure is chronic mountain sickness. Chronic mountain sickness is characterized by erythrocytosis, neurologic symptoms, pulmonary hypertension, and cor pulmonale (Villafuerte, 2015).

It is proposed that chronic exposure to high altitude is also associated with systemic hypertension. However, the data supporting this association is murky with many limitations. In a meta-analysis of cross-sectional studies from Tibet, a 2% increase in prevalence of hypertension is seen with every 100 m increase in altitude (Mingji et al., 2015). A second meta-analysis finds similar results in the Tibetan populations (Aryal et al., 2016). The impact of these studies is difficult to take at face value due to the limited available data in this field, the inclusion of cross-sectional studies, the lack of patient-level data, and variation in patient characteristics between the studies included. In a study from Japan, elevated diastolic blood pressure is seen in high-altitude populations (Otsuka et al., 2005). This finding is difficult to interpret as they compared a low-altitude population from a single community in Japan to a high-altitude community from Ladakh. Recent studies from China show an increased risk of hypertension in high-altitude populations. However, these individuals also have multiple comorbidities that increase the risk for developing hypertension such as active smoking, obesity, and poor lifestyle (Shen et al., 2017; Yue et al., 2017). In contrast to these findings, some studies have found a null or beneficial effect of altitude on hypertension. A study evaluating trekkers with and without hypertension shows that both systolic and diastolic blood pressures remain stable with exposure to high altitude. However, there are participants in both groups that experienced severe, asymptomatic hypertension with an unclear consequence (Keyes et al., 2017). A major limitation of this study is that blood pressure measurements began once the participants had reached 2860 m with no sea level blood pressures available for comparison.

An evaluation of urban, semiurban, and rural populations from Peru finds a lower incidence of hypertension among those living at high altitudes. The high-altitude population studied also has a lower incidence of obesity, a known risk factor for developing hypertension, introducing confounding into the interpretation of the results. In addition, other factors that may influence obesity and hypertension were not evaluated thoroughly in this study such as lifestyle factors and access to healthcare (Bernabe-Ortiz et al., 2017). While many more studies exist evaluating the link between hypertension and exposure to chronic hypoxia, these studies highlight the controversy in proclaiming an association between these entities and provide an area for future research.

In terms of high-altitude pulmonary hypertension, little information is available on the prevalence of this disease. Some of the difficulty in studying this disease arises from the overlap in symptoms between high-altitude pulmonary hypertension and other lung diseases and the requirement of invasive hemodynamics for definitive diagnosis. A more in-depth review of the relationship between altitude exposure and lung disease can be found in the review by Grissom and Jones in this issue. The negative effects of altitude are also seen in several other disease conditions. In terms of individuals with known CAD, exposure to hypoxia alone is not sufficient to cause ischemia, but diseased segments of the coronary artery fail to exhibit hypoxia-induced vasodilation (Karliner et al., 1985; Malconian et al., 1990; Arbab-Zadeh et al., 2009). Additional research in this area is needed to clarify the safety of exposure to prolonged hypoxia in these patients.

In animal studies, rats exposed to chronic hypoxia exhibit increased plasma and hepatic triglycerides (Siques et al., 2014). Elevated triglycerides are also seen in a study of army men exposed to chronic intermittent hypoxia (Brito et al., 2007). In high-elevation populations in Peru, higher body mass index and lower pulmonary function are associated with lower resting daytime oxyhemoglobin saturation. Lower resting daytime oxyhemoglobin is associated with higher odds of having metabolic syndrome, insulin resistance, higher hemoglobin A1c levels, and higher high-sensitivity C-reactive protein levels (Miele et al., 2016). In addition, high-altitude populations are at risk for developing high-altitude renal syndrome, which is characterized by polycythemia, hyperuricemia, systemic hypertension, and microalbuminuria with preserved glomerular filtration rate (Hurtado et al., 2012). Decreased glomerular filtration rate is seen with chronic intermittent altitude exposure (Brito et al., 2007).

Hypoxia as a Potential Therapeutic

Animal studies demonstrate a favorable effect of exposure to hypoxia on CVD. In contrast to the adult mammalian heart, which is one of the least proliferative organs, some vertebrate species, such as zebrafish, have a remarkable capacity for heart regeneration (Poss et al., 2002). This regenerative capacity is largely driven by continuously cycling cardiomyocytes rather than cell cycle-arrested cardiomyocytes, which populate the adult mammalian heart. In addition, zebrafish and adult mammals have significant physiologic differences. The zebrafish heart is exposed to a hypoxic environment due to the mixing of arterial and venous blood (Nikinmaa, 2002). Studies of the neonatal mammalian heart establish a short window of time immediately after birth, in which significant cardiomyocyte proliferation can occur even after injury. Cardiac injury that occurs after this window has passed results in fibrosis and scar formation (Porrello et al., 2011, 2013; Xin et al., 2013; Aurora et al., 2014; Bryant et al., 2015; Darehzereshki et al., 2015; Mahmoud et al., 2015; O'Meara et al., 2015; Polizzotti et al., 2015; Xiao et al., 2017).

In adult mice, exposure to chronic hypoxia equivalent to the summit of Mount Everest leads to decreased mitochondrial reactive oxygen species production and reduced oxidative DNA damage. It also induces hyperplastic growth of the heart by evidence of increased cell cycle activity and increased total cardiomyocyte number. After myocardial infarction, adult mice exposed to hypoxia show significant myocardial recovery with increased coronary collaterals, improvement in ejection fraction, and reduced scar formation. Several contributing factors likely underlie this improvement. Chronic hypoxia alters mitochondrial metabolism with reduction of enzymes involved in the Krebs cycle and fatty acid β-oxidation. As previously described, HIF1α expression is stabilized with chronic hypoxia. In addition, a number of metabolic pathways are significantly dysregulated in the hypoxia group (Nakada et al., 2017). While the data from this study demonstrates a potential role for hypoxia as a therapeutic strategy for cardiac recovery after myocardial infarction, further studies are needed to gain a better understanding of the mechanisms driving improvement in cardiac function

In addition, there are multiple barriers to translating these findings to humans who have sustained a previous myocardial infarction. Although altitude-like conditions can be simulated in a variety of ways, it has only been applied in human trials as an intermittent condition. Developing a protocol or device for chronic exposure that can be applied to patients after myocardial infarction for weeks at a time is a challenge that will need to be surmounted to make this an accessible and viable therapy. It is also not clear that the benefits of hypoxia therapy in this patient population will outweigh the possible adverse effects that come with the physiologic changes that we outlined earlier in this review. Further work in this field is needed to develop a feasible treatment strategy that harnesses the beneficial effects associated with chronic hypoxia for individuals with CAD.

Conclusions

A number of studies have been published evaluating the impact of living at altitude on the development of CVD and related diseases such as dyslipidemia, obesity, and hypertension. Many of the initial studies in this field have conflicting findings driven by significant confounding. More recent studies that have addressed many of these confounders have demonstrated the beneficial effects of hypoxia on CVD and risk factors for CVD. However, this benefit comes at the risk of developing several conditions that are potentially associated with acute and chronic exposure to high altitude such as high-altitude pulmonary edema, pulmonary hypertension with possible heart failure, and renal disease. Interestingly, animal data have demonstrated the significant positive effects of exposure to extreme hypoxia after myocardial infarction. More research is needed to define the mechanism driving the positive effects of hypoxia that it can potentially be applied to larger populations while mitigating the negative effects.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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