1. Introduction

Cardiovascular diseases (CVDs) are the leading cause of premature death and disability globally. These include ischemic heart disease (IHD), also known as coronary artery disease (CAD), and atherosclerotic cardiovascular disease (ACD) [1]. According to the World Health Organization (WHO), ischemic heart disease (IHD) was responsible for over 17.9 million deaths in 2019. In the same year, IHD accounted for more than 180 million disability-adjusted life-years (DALYs) and led to the loss of over 175 million years of life due to premature mortality [2, 3]. In Europe, ischemic heart disease (IHD) continues to be the most significant cause of death, accounting for over 860,000 deaths in men and nearly 880,000 deaths in women each year. In Brazil, the IHD landscape has evolved dramatically over the years, with the number of affected individuals soaring from 1.48 million in 1990 to over 4 million in 2019 [4–6]. In Ecuador, data reveals that between 2001 and 2016, there were 46,133 IHD-related deaths, with men constituting 60% of these fatalities [7]. Moreover, IHD was the leading cause of death in Ecuador in 2019 and 2020, and it ranked second in 2021 and 2022, only outpaced by COVID-19 [8, 9].

In terms of etiology, myocardial oxygen supply can be compromised by factors leading to hypoxia, anoxia, or infarction [10]. While traditional risk factors like smoking, obesity, and diabetes predominantly contribute to atherosclerosis in coronary arteries, non-traditional risk factors such as hypoxia and exposure to high altitudes remain relatively understudied [2, 11–13]. Given that millions globally reside at altitudes exceeding 2,500 meters in geographically diverse regions like the South American Andes, Central Asia’s Karakorum-Pamir and Himalayan ranges, and the Ethiopian Highlands in East Africa, exploring high-altitude exposure as a risk factor for ischemic heart disease (IHD) is essential [14]. Theoretically, patients with coronary artery disease (CAD) and angina may be more adversely affected by high-altitude (HA) exposure due to pre-existing factors such as increased basal coronary flow, impaired arterial elasticity due to atheromatous lesions, and microvascular dysfunction [15–18]. Conversely, in healthy individuals, high-altitude exposure may induce coronary arterial vasodilation and increased blood flow, angiogenesis and therefore could potentially enhance resilience to hypoxic events [19–21].

In recent years, emerging evidence has enhanced our understanding of the interplay between ischemic heart disease (IHD) and high-altitude exposure, particularly concerning asymptomatic IHD patients and those who have undergone revascularization [18]. However, the question remains as to whether high altitude serves as a protective factor or increases the risk of infarction, especially in newcomers [22, 23].

This study aims to examine acute myocardial infarction and other ischemic heart diseases in Ecuador, a unique country with 221 cities spanning elevations from sea level to over 4,300 meters. The study serves dual purposes: it assesses the impact of ischemic heart disease within Ecuador and contributes to our understanding of the disease’s burden at varying altitudes. By doing so, it adds a critical piece to the puzzle of understanding the relationship between elevation and cardiac disease.

2. Materials and methods

3. Results

3.2 Incidence

During the analyzed period (2011–2021), the overall sex-specific adjusted incidence rate of ischemic heart disease was higher in men, with 55.08/100,000 compared to 20.77/100,000 in women. The age groups most affected were patients between 75 and 79 years old and those over 80 years of age, with the highest incidence rates observed in both sexes. Furthermore, 90% of women patients and 88% of men patients admitted to the hospital for ischemic heart disease were older than 50 years of age (Table 1).

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Table 1. Displays the incidence and mortality rates of ischemic heart disease in Ecuador from 2011 to 2021 according to different age categories and gender.

https://doi.org/10.1371/journal.pone.0295586.t001

From 2011 onwards, the annual incidence of IHD, estimated using hospital admissions as a proxy, has been on average 39.3 per 100,000 for men and 15.5 per 100,000 for women (S1 Checklist). Notably, in 2020, during the onset and first waves of the COVID-19 pandemic, the incidence rate of cardiac ischemia showed a sharp decrease, reaching its lowest level in recent years at 31.6 per 100,000 for men and 12.1 per 100,000 for women (Fig 1).

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Fig 1.

A illustrates the gender-specific trend in incidence rate of ischemic heart disease from 2011 to 2021. Men consistently had a higher incidence rate than women during this period, with a slight decrease observed for both genders in 2020. B shows the mortality rate of ischemic heart disease, with a significant increase in 2020–2021 compared to previous years. Men had a consistently higher mortality rate than women.

https://doi.org/10.1371/journal.pone.0295586.g001

3.3 Mortality

From 2011 to 2021, the mortality rate for ischemic heart disease, based on death certificates, was 47.2 per 100,000 for men and 34.8 per 100,000 for women on average. However, in 2020 there was a significant increase of approximately 121.4% in men (with a mortality rate of 104.5 per 100,000) and approximately 119.8% in women (with a mortality rate of 76.5 per 100,000). When considering in-hospital mortality, the average percentage of patients with ischemic heart disease who died was 8.7% for men and 13.8% for women. Acute myocardial infarction had the highest in-hospital mortality rate for both sexes, with a rate of 13% for men and 21.7% for women (Fig 2).

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Fig 2. Shows the in-hospital mortality rate (%) by cause for men and women from 2011 to 2021.

Except for certain current complications following acute myocardial infarction, women had higher mortality rates than men for all causes.

https://doi.org/10.1371/journal.pone.0295586.g002

3.5 Geodemographic distribution

3.5.1 Province distribution.

The incidence rates of ischemic heart disease were highest in the Galapagos (167.7 / 100,000), Manabí (75.48 / 100,000), and Pastaza (72.43 / 100,000) provinces, while the lowest rates were found in Cotopaxi, Esmeraldas, and Chimborazo provinces with 26.68 / 100,000, 27.29 / 100,000, and 34.15 / 100,000, respectively (Table 2). In terms of mortality, Galapagos and Guayas provinces had the highest mortality rates with 180.7/100,000 and 92.47/100,000, respectively (Table 2).

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Table 2. Incidence and mortality rates for ischemic heart disease in Ecuadorian provinces from 2011 to 2021, by province.

The provinces with the highest incidence rates for ischemic heart disease in Ecuador from highest to lowest are Galapagos, Manabí, and Cotopaxi. The provinces with the highest mortality rates for ischemic heart disease in Ecuador from highest to lowest are Orellana, Pastaza, and Galapagos.

https://doi.org/10.1371/journal.pone.0295586.t002

3.5.2 Cantonal distribution.

According to the patient’s recorded place of residence, the cantons in Ecuador with the highest incidence rates per 100,000 population for IHD were Aguarico, Paquisha, and Yacuambi with rates of 2,552.26, 1,970.58, and 1,782.82, respectively. On the other hand, the cantons with the lowest incidence rates were Quininde, Otavalo, and Mejia with rates of 37.88, 38.59, and 43.26, respectively.

In terms of mortality rates per 100,000 population, the cantons with the highest rates for IHD were Exterior, Crnel. Marcelino Mariduena, and Olemdo with "Inf" indicating an undefined value. In contrast, the cantons with the lowest mortality rates were Quito, Cuenca, and Tena with rates of 46.82, 52.72, and 59.18, respectively (Fig 3).

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Fig 3. Spatial analysis of ischemic heart disease in Ecuador at the cantonal level (2011–2021).

A) Incidence rate per 100,000 population, illustrating the distribution of ischemic heart disease across 221 cantons. B) Mortality rate per 100,000 population, revealing the patterns of fatal outcomes across the same 221 cantons.

https://doi.org/10.1371/journal.pone.0295586.g003

3.6 Altitude analysis

The analysis of ischemic heart disease incidence and mortality rates in relation to altitude reveals distinct patterns. At low altitudes (<2500 m), the average incidence rate is 61.65, and the average mortality rate is 121.8. In contrast, at high altitudes (>2500 m), the average incidence rate drops to 25.9, and the average mortality rate decreases to 38.5 (Fig 4). These findings suggest that both the incidence and mortality rates of ischemic heart disease are significantly higher at lower altitudes compared to higher altitudes (Fig 4).

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Fig 4.

A) Incidence rate of ischemic heart disease per 100,000 population across the four altitude categories: low (<1,500 m), moderate (1,500 m to 2,500 m), high (2,500 m to 3,500 m), and very high (3,500 m to 5,500 m), B) Mortality rate of ischemic heart disease per 100,000 population in men and women categorized in low (<1,500 m), moderate (1,500 m to 2,500 m), high (2,500 m to 3,500 m), and very high (3,500 m to 5,500 m). C) Incidence rate categorized by low (<2,500 m) and high (>2,500 m) altitude. D) Mortality rate of ischemic heart disease per 100,000 population in men and women, categorized by low (<2,500 m) and high (>2,500 m) altitude.

https://doi.org/10.1371/journal.pone.0295586.g004

3.6.1 Age and sex differences at different altitudes.

The analysis of ischemic heart disease incidence and mortality rates in relation to altitude and gender reveals considerable differences. At both low and high altitudes, men have substantially higher incidence rates compared to women, with a percentage difference of 138.7% at low altitudes and 150.0% at high altitudes. Mortality rates also exhibit disparities, although less pronounced, with men showing a 48.3% higher rate at low altitudes and a 23.2% higher rate at high altitudes compared to women (Table 3).

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Table 3. Ischemic heart disease incidence and mortality rates according to different altitudes from 2011 to 2021.

https://doi.org/10.1371/journal.pone.0295586.t003

As expected, the incidence of the disease increases with age for both men and women at any altitude. The highest rates are observed in the 80+ age group, particularly in the low altitude range, with men experiencing a rate of 936.11 per 100,000 individuals and women showing a rate of 789.63 per 100,000 individuals. This trend of higher rates among men compared to women is consistent across all age groups and altitude ranges. The percentage difference between very high altitude compared to low altitude is 97.71% for men and 97.11% for women. This significant difference indicates that the incidence of ischemic heart disease is much higher in individuals living at low altitudes compared to those living at very high altitudes (Fig 5).

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Fig 5.

A) Age-specific incidence rates of ischemic heart disease per 100,000 population, stratified by sex and altitude categories (low, moderate, high, and very high). B) Age-specific mortality rates of ischemic heart disease per 100,000 population.

https://doi.org/10.1371/journal.pone.0295586.g005

4. Discussion

In this study, we have presented one of the very first comprehensive analysis of the burden of ischemic heart disease across distinct elevation ranges using countrywide data. The initial observation that drew our attention was the decline in incidence during the first year of the pandemic in Ecuador. Both men and women experienced reduced access to healthcare systems, which likely contributed to the reduced hospital admission but the sharp increase in IHD related-mortality [28]. This increase was inversely proportional to hospitalization rates, suggesting that a higher number of individuals fell ill, but due to limited access to hospitals, more people died without receiving medical care [29]. Furthermore, this trend could be associated with the surge in excess mortality observed during the COVID-19 pandemic [30]. Related to high altitude exposure, the country’s diverse topography, with 221 cities situated from sea level up to 4,300 meters (very high altitudes), offers a unique opportunity to investigate the impact of altitude on the epidemiology of chronic diseases such as ischemic heart disease (IHD) or stroke [31, 32], for example, Freire et al. stated that the main reasons for Galapagos being one of the provinces of Ecuador with the highest rates of overweight and obesity is the increased consumption of ultra-processed foods and decreased consumption of traditional cooking based in unprocessed and minimally processed foods, mainly due to the greater ease of access to this type of food by the inhabitants of the islands [33], their findings could justify, at least partially, the higher rates of coronary heart disease triggered by metabolic alterations in this population [34].

The assessment of the geographical distribution of ischemic heart disease across Ecuador provides critical insights into the prevalence and impact of this condition in a setting where it has been under-researched. While our study highlights distinct epidemiological variations in incidence and mortality rates between populations at lower and higher altitudes, it is crucial to consider several confounding variables. Factors such as poverty, limited healthcare access, dietary habits, and smoking may influence these rates. Despite recognizing these limitations, it is important to note that obtaining more comprehensive data in Ecuador is particularly challenging due to data unavailability or restricted access. Nonetheless, we discovered that the provinces of Ecuador with the highest incidence of ischemic heart disease were Galápagos, Manabí, and Pastaza. These provinces are located at low altitudes, where it seems that certain risk factors may have a stronger influence on the development of both ischemic heart disease and stroke [31, 35]. Interestingly, a study carried out in the Swiss population suggest potential explanations for the lower mortality from coronary heart disease (CHD) and stroke at higher altitudes. These authors suggest that some behavioral cardiovascular diseases (CVD) risk factors, such as smoking, poor diet, and physical inactivity, could be more common at lower altitudes, although the same study advises that these risk factors do not differ substantially by altitude [20, 35].

In Ecuador, epidemiological data reveals key risk factors for ischemic heart disease (IHD). Specifically, 10% of the population aged 18–69 are tobacco users, while 60% face issues related to overweight or obesity, most prominently between the ages of 40 and 50. Galapagos province exhibits the highest obesity rate at 15.09% [36–38]. Moreover, 19.8% of Ecuadorians are hypertensive; among them, 17% have uncontrolled hypertension and 56.3% are without medication. Pan American Health Organization data further indicate that 10% of individuals aged 50–59 suffer from diabetes, and 50% have elevated cholesterol levels. Importantly, these studies lack controls for altitude and canton of residence, variables that may influence the prevalence of these risk factors [39, 40].

The disparate mortality rates between high-altitude and low-altitude residents remain not fully elucidated. However, lifestyle and environmental factors unique to higher altitudes could contribute. Recent research suggests that conditions predisposing to hypoxia, such as sleep apnea, may confer cardioprotective effects through mechanisms like myocardial angiogenesis [41–44]. In this context, we hypothesize that the reduced partial pressure of oxygen at higher altitudes may confer protective cardiovascular effects. This hypothesis is informed by animal studies demonstrating that chronic hypoxia induces angiogenesis, thereby enhancing the brain’s resilience to ischemic hypoxia [19, 21, 42]. In fact, intermittent exposure to hypobaric hypoxia has been proposed, and successfully applied, for the improvement of myocardial perfusion both in people and in experimental animal models [44, 45]. Other research posits that residents of high-altitude regions may adopt healthier lifestyles, such as regular physical exercise and improved dietary habits, possibly influenced by the region’s demanding climate and geography. These lifestyle factors could contribute to enhanced cardiovascular health [46, 47]. Other factors, such as increased exposure to ultraviolet radiation and higher levels of vitamin D synthesis at higher altitudes, may also play a protective role against cardiovascular disease, but more investigation is needed [48]. This liposoluble vitamine exerts cardio-protective effects by modulating blood pressure through its action on endothelial and smooth muscle cells [48]. A deficiency in vitamin D has been implicated in vascular dysfunction, increased arterial stiffness, and left ventricular hypertrophy, according to current scientific literature [48–50].

Despite uncertainties in the underlying mechanisms that might reduce the risk of ischemic heart disease (IHD), our study clearly demonstrates a higher prevalence of IHD and associated mortality at lower altitudes, after adjustments for population, age, and sex. These results align with findings from other studies conducted in high-altitude locations. For instance, Lopez-Pascual et al., who studied an Ecuadorian population and found lower prevalence rates of metabolic syndrome, hypercholesterolemia, and hyperglycemia among adults with a high educational level living at 2,754m compared to inhabitants of the Ecuadorian lowland coast region [51]. These results together with those reported by Freire et al. [33], suggest that lifestyle and environmental factors associated with living at low altitudes, such as dietary patterns, sedentary but stressful urban life or different habits and access to healthcare, may contribute to the higher mortality rates observed in our study [51]. Other authors have compared this phenomenon in other populations, finding a greater relationship of hypercholesterolemia with socioeconomic and sociocultural level and lifestyles rather than with altitude [52].

While our study found that mortality rates caused by cardiovascular disease are generally lower at higher altitudes, it is important to note that at altitudes greater than 3,500m, stroke mortality rates increase again and may surpass those observed in moderate-lying areas [31]. This finding suggests that physiological responses to permanent life at high altitude may have their limits (at least in Andean people) and due to extremely high blood viscosity could have negative effects on tissue oxygenation. Other studies have also pointed out the relationship between extreme altitudes above 3,000m and increased mortality in general, which may be due to factors such as decreased oxygen availability and increased exposure to extreme weather conditions [52].

Our study, focusing on a wide range of altitudes including regions at extreme elevations, complements existing literature which mostly reports cardiovascular data from moderate altitudes [52]. Altitude-related genetic and metabolic adaptations may influence cardiovascular health, but their mechanisms remain incompletely understood [53]. While studies suggest that altitude-specific behaviors may affect metabolism and energy efficiency [51]. the role of factors like hypoxia-induced angiogenesis or hemoglobin levels varies across populations and can even differ within high-altitude communities [53–55].

According to our findings, we cannot assert a consistent dose-response relationship between high altitude, although a reduced risk of developing ischemic heart disease seems apparent between 2,000m and 3,500m of elevation. However, beyond this altitude range, other factors might be involved in an increase of harm effect.

5. Limitations

Our research is primarily based on INEC’s publicly accessible databases, bringing with it inherent limitations related to data accuracy and completeness. We were not able to verify the initial data, rendering our results susceptible to biases stemming from data entry errors or incomplete reporting.

One significant constraint is the absence of control for key risk factors such as body mass index, blood pressure levels, smoking status, alcohol consumption, diabetes, a sedentary lifestyle, cholesterol, and triglyceride levels. This is due to the unavailability of these data points. The inability to adjust for these factors inherently limits the precision of our risk estimations.

Another limitation is that our dataset does not provide the granularity needed to identify individual patients who might have utilized healthcare services in multiple locations at different times, potentially resulting in duplicated data entries.

We also lacked the necessary information to employ a proportional hazards model for survival rate estimations, which limits the depth of our statistical analyses.

Our study’s ecological design further restricts our ability to establish causal relationships between variables.

Additionally, the regional limitations of our data set mean that our findings may not be generalizable to other geographic areas or populations, especially those with significantly different healthcare infrastructures or cultural attitudes toward healthcare.

Moreover, the study did not consider seasonal variations, which might influence ischemic heart disease incidence and mortality, nor did it account for healthcare quality, which could have differential impacts at various altitudes.

Lastly, although our study identifies correlations between altitude and ischemic heart disease, it does not delve into underlying biological mechanisms, leaving this as a subject for future research.

By acknowledging these limitations, we aim to adhere to academic rigor and offer transparent insight into the potential scope and constraints of our study. This also provides a roadmap for future research in this area.

6. Conclusions

Our investigation sheds light on the intricate relationship between altitude and mortality attributable to ischemic heart disease (IHD). While our data suggest that elevated altitudes may exert a protective effect against IHD, the relationship between altitude and cardiovascular health appears to be multifaceted and potentially dependent on specific altitude ranges. Although a consistent dose-response relationship was not observed in our study, it is imperative that future research explores additional variables, including dietary habits, alcohol and tobacco use, and physical activity levels, which could influence cardiovascular risk.

Our findings hold particular relevance for high-altitude populations in the Andean regions, offering insights that could guide targeted interventions to alleviate disease burden. In summary, our research underscores the critical need for further studies to comprehensively understand the effects of altitude on cardiovascular health, as well as the interactions with various modifiable and non-modifiable risk factors.

Supporting information

Acknowledgments

We express our gratitude to the National Institute of Statistics and Census for making their data publicly available and facilitating our research endeavors.