Mohamed Ali Al-Huthi, MBChB, MSc; Yahia Ahmed Raja'a, MBChB, MSc, PhD; Mohammed Al-Noami, MBChB, MSc, PhD; Abdul Rashid Abdul Rahman, MBChB, PhD, FRCPI, FRCPEd 

Medscape General Medicine.  2006;8(4):28.  ?2006 Medscape

 

Background: A comparative retrospective study was performed to compare the distribution of risk factors and complications in patients with acute coronary syndrome (ACS) at high-altitude vs low-altitude areas in Yemen.
Methods: The records of 768 patients from Sana'a (high altitude) and Aden (low altitude) were reviewed. Risk factors assessed were age, hypertension, diabetes mellitus, hyperlipidemia, cigarette smoking, and reported history and family history of coronary artery disease (CAD). Complications of ACS of interest were heart failure, arrhythmias, cerebrovascular accident (CVA), and death.
Results: The mean age of ACS patients at high altitude was significantly lower than those at low altitude (55.3 years [SD = 8.2] vs 56.8 years [SD = 7.1]; P = .007). History of hyperlipidemia was significantly higher in high-altitude patients than in low-altitude patients (49.2% vs 38.3%; odds ratio [OR] = 1.563; P = .002). Reported history of CAD was also significantly higher at higher altitudes (16.7% vs 9.4%; OR = 1.933; P = .003). Previous history of diabetes mellitus and tobacco smoking was slightly higher with borderline significance. Hypertension and reported family history of CAD were comparable among high- and low-altitude patients. In terms of in-hospital complications, CVAs were significantly higher in high-altitude patients than in low-altitude patients (7.8% vs 4.4%; P = .0001). Heart failure, arrhythmias, and death rates were comparable in both groups of patients. Wall motion abnormalities were comparable, whereas the ejection fraction was lower in the high-altitude patients (49.8% [SD = 16.08] vs 54.8% [SD = 16.23]; P = .0001).
Conclusions: ACS occurs at a younger age at high altitudes. Patients who live in high-altitude regions are also more likely to have hyperlipidemia and a previous history of CAD. Stroke and reduced left ventricular ejection fraction (LVEF) occur more commonly in high-altitude ACS patients. High altitude may generally be a risk factor for ACS.

Introduction

Coronary artery disease (CAD) is a well-established major cause of death and disability in both developed and developing countries.^[1] CAD continues to be the leading cause of morbidity and mortality among adults in Europe and North America.^[2] Twelve million individuals in the United States and 143 million worldwide have CAD.^[3] Although cardiovascular mortality has been diminishing in all of Western Europe and North America for the past decades, it is still one of the major contributors to mortality, especially premature death.^[4] Regardless of declines in developed countries, both CAD mortality and the prevalence of CAD risk factors continue to rise rapidly in developing countries.^[5,6] Traditional risk factors for CAD are age, male sex, family history, diabetes mellitus, dyslipidemia, hypertension, obesity, and tobacco smoking. These risk factors are useful for assessment of an individual's cardiovascular risk.^[7] Many other risk factors, however, are still under scientific scrutiny.^[8,9] Several studies have shown that classic risk factors partially explain the prevalence of CAD.^[10-12] Regardless of reported sizable geographic variation in CAD occurrence and outcomes, only a few environmental contributors have been identified. Differences in environmental and genetic factors lead to differences in the incidence of CAD worldwide.^[13] Geographic variations in CAD have been explained by variations in major risk factors and/or socioeconomic factors in a number of studies, but some variation tends to remain, even after controlling for these factors. Disparities in cardiovascular outcomes across geographic regions are common, but not yet well understood.^[14]

One environmental risk factor that may contribute to CAD is altitude: Evidence for this is so far conflicting. Many studies have examined risk-factor profiles for CAD in populations at high- and low-altitude regions. Results have shown that there are differences in the prevalence of CAD and its risk factors at different altitudes. Such disparities in outcomes provide incentives to further investigate the influence of altitude on CAD and the risk for CAD in a country, such as Yemen. Is living at a high altitude a risk for ACS, and is the prevalence of risk factors for ACS and its complications influenced by altitude?

A Peruvian study reported that the prevalence of hypertension at high altitude was lower than in a low-altitude population.^[15] A study in central Asia agreed with the Peruvian study. It demonstrated that hypertension was more prevalent at lower altitudes than at higher altitudes.^[16] A Russian study on high altitude reported that hypertension was significantly higher among residents in a low-altitude region compared with residents in a high-altitude region.^[17]

On the other hand, other studies have reported opposite results: A study in the United States has shown that high-altitude living is associated with elevated blood pressure.^[18] An Italian study agreed with the American study; it reported that the mean values of systolic and diastolic blood pressures were higher among mountain residents than lowlanders.^[19] US researchers concluded that higher altitudes may increase the risk for atherosclerotic cardiovascular disease.^[20] On the other hand, an Indian study reported opposite results; total cholesterol decreased with increasing altitude, whereas high-density lipoprotein cholesterol (HDL-C) increased.^[21] However, the aforementioned central Asia study reported that the serum lipid levels did not differ between populations in low- and high-altitude areas.^[16] A study that was conducted on Tibetans demonstrated lower serum lipid levels with a low incidence of CAD with high-altitude living.^[22] A Spanish study reported that HDL-C levels were linearly and significantly increased with high-altitude living.^[23] A Venezuelan study reported that men and women living at higher altitudes had significantly lower plasma total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, and slightly lower HDL-C levels than those at lower altitudes.^[24]

There is a lack of data on the effects of altitude on Middle Eastern populations. A study in Saudi Arabia demonstrated that populations living at higher altitudes have a higher prevalence of hypertension, CAD, diabetes mellitus, and tobacco smoking than populations living at lower altitudes.^[25] Another study in Saudi Arabia showed that serum cholesterol, LDL-C, hematocrit, and obesity were more prevalent in high-altitude populations than in low-altitude populations, and blood pressure was significantly higher in highlanders compared with lowlanders.^[26] Another study in Saudi Arabia reported that men and women who were 45 years old and above living at high altitude had a significantly higher risk of developing hypertension compared with those living at sea level.^[27]

Most of the previous studies (Russian, Italian, Peruvian, Spanish, Venezuelan, and Saudi Arabian) investigated 1 or 2 risk factors for CAD in a population of heterogeneous ethnicity. This provided us with the incentive to further investigate the association of cardiovascular risk factors and altitude in a country, such as Yemen, where the population is predominantly of the same ethnicity, which enables us to establish the independent role of altitude on the prevalence of risk factors for CAD. One way of doing this is to study patients with documented cardiovascular events. This not only allows us to investigate altitude as an independent risk factor for CAD, but also enables us to study whether differences exist in clinical characteristics of patients with established CAD at different altitudes.

Objective: The objective was to estimate the prevalence of risk factors in patients with ACS in high- vs low-altitude areas, and to investigate the clinical presentation and complications of ACS among high- vs low-altitude patients.

Methodology: A comparative retrospective study design was employed for this study.

Population sample: This study was done on diagnosed adult ACS Yemeni patients aged 30-69 years residing in high- and low-altitude areas. The lifestyles were almost comparable in the two populated areas, except for dietary habits: Coastal people mostly consume seafood and rice, whereas high-altitude people consume cereals, poultry, and red meat.

For the high-altitude region, we collected data from all ACS patients admitted consecutively to the cardiac care unit (CCU) in Al Thawra General Teaching Hospital in Sana'a from February 2004 to December 2004.

For lower altitudes, we collected data from all ACS patients admitted consecutively to CCU in Al-Jumhuriyah Teaching Hospital in Aden from July 2003 to December 2004.

Study area: High altitude -- the area between 1500 and 3500 m above sea level.^[28]

Case selection: We selected ACS patients admitted to the CCU and had diagnosis of ACS according to the World Health Organization (WHO) criteria for the diagnosis of ACS. Records of consecutive patients were reviewed retrospectively.

Diagnosis of ACS followed the WHO criteria. It required at least two of the following 2 elements: acute myocardial infarction (AMI) with ST elevation (typical symptoms or electrocardiogram [ECG] with ST elevation and raised creatine kinase [CK]-MB isoenzyme or troponin), AMI without ST elevation (typical symptoms or ECG without ST elevation and raised CK-MB isoenzyme or troponin), and unstable angina (symptoms or ECG indicative of ischemia, with normal enzymes).^[29]

We selected all ACS cases admitted at:

Both hospitals are the main referral hospitals for the residents in the 2 areas and adjacent governorates. They have staffs with similar experience. The specialists in Al Thawra Hospital belong to the Faculty of Medicine, Sana'a University, and the specialists in Al-Jumhuriyah Hospital belong to the Faculty of Medicine, Aden University. The 2 hospitals have the same regimen for managements of ACS. The facilities in both CCUs are similar. Both hospitals receive cases from all socioeconomic classes. In Al Thawra Hospital (Sana'a), there is a cardiac center that is partially separated from Al Thawra Hospital. It is the only cardiac center in Yemen. It includes a cardiac surgery center, a pediatric cardiac surgery ward, and 1 cath lab for coronary angiography and angioplasty. It receives patients who need cardiac surgery or angioplasty from all over the country.

Exclusion criteria: Other cardiac diseases (congenital heart disease, rheumatic heart disease, and noncoronary cardiac surgery), chronic medical illness (eg, end-stage liver/renal failure), and malignancies.

Sample size: A total of 768 patients who were admitted in the CCU as cases of ACS at high- and low-altitude hospitals were studied. Three hundred eighty-four patients were from high altitudes and an equal number were from low altitudes.

Investigations protocol: The following data were collected.

Statistical analysis: Data were analyzed by an SPSS program to calculate percentages and mean ? SD. The 2-tailed test was used to assess the differences between continuous variables. Chi-squared tests were used to compare categoric variables. Odds ratios (ORs) were calculated. Data are presented as means (SD). We set the level of the statistical significance at a P value of less than .05. Statistical tests with P < .10 and P > .05 were considered to be of borderline significance.

Results

Age and Clinical Diagnosis

The mean age of the high-altitude ACS patients was significantly lower than the low-altitude patients (55.3 years [8.2] vs 56.8 years [7.1]; P = .007) ( Table 1 ). There was slightly more AMI at higher altitudes, whereas the opposite was true for unstable angina. The differences were, however, not significant ( Table 2 ).

Clinical Presentation

There was no difference in clinical presentation of the high- and low-altitude patients. Heart rate in the high-altitude patients was significantly higher than in the low-altitude patients (89 beats/minute [17.5] vs 83 beats/minute [16.8]; P < .000) ( Table 1 ). Systolic blood pressure at high altitude was significantly higher than in the low-altitude patients (135 mm Hg [SD 24.9] vs130 mm Hg [23.2]; P < .013). Diastolic blood pressure was also significantly higher among the high-altitude patients (84 mm Hg [16.7] vs 81 mm Hg [17.7]; P = .009) ( Table 1 ).

Prevalence of History of CAD Risk Factors

The prevalence of history of hyperlipidemia was significantly higher at higher altitudes than at lower altitudes (49.2% vs 38.3%; adjusted OR = 1.563; P = .002) ( Table 3 ). The prevalence of reported history of CAD at high altitude was significantly higher than in low-altitude patients (16.7% vs 9.4%; adjusted OR = 1.933; P = .003) ( Table 3 ). Past history of diabetes mellitus was slightly higher (borderline significance) (30.7% vs 25.3%; P = .091); also, history of tobacco smoking was slightly higher with borderline significance (64.1% vs 57.8%; P = .076).

The prevalence of history of hypertension was comparable at both altitudes (49.2% vs 45.1%; P = .24). Reported family history of CAD was comparable at both altitudes (17.2% vs 15.4%, P = .49) ( Table 3 ).

In-hospital Complications

Cerebrovascular accidents (CVA) were significantly higher in the high-altitude patients than in the low-altitude patients (7.8% vs 4.4%; adjusted OR = 1.830; P < .0001). Death, heart failure, and arrhythmias were all nonsignificantly higher in the high- vs low-altitude patients (Figure). Wall motion abnormalities detected by echocardiography were more frequently seen in patients at higher altitudes compared with lower altitudes (79.2% vs 73.2%; P = .51) ( Table 4 ). The ejection fraction was significantly lower in the high-altitude patients (49.8% vs 54.8%; P = .0001) (Figure).

Figure. 

In-hospital complications in acute coronary syndrome Yemeni patients at high and low altitude (N = 768).

     

Laboratory Findings

Hematologic findings. Hemoglobin among ACS patients at high altitude was significantly higher than in the low-altitude patients (15.4 g/L [1.8] vs 13.2 g/L [1.2]; P < .0001) ( Table 5 ). Hematocrit was also significantly higher among ACS patients at higher altitudes (45.7% [5.1] vs 39.9% [3.6]; P < .0001) ( Table 5 ). Leukocyte count (white blood cell count) was significantly higher among ACS patients at higher attitudes than at lower altitudes (P < .000) ( Table 5 ).

Biochemical findings. Table 6 summarizes the biochemical findings: CK at higher altitudes was significantly higher than at lower altitudes, as well as CK-MB. Total serum cholesterol and triglycerides at higher altitudes were significantly higher than at lower altitudes. LDL-C was higher, whereas HDL-C was significantly lower for the high-altitude patients. Both fasting and random blood glucose were significantly higher for the high-altitude ACS patients.

Discussion

Our study was performed on 768 ACS Yemeni patients, in high- and low-altitude regions. Their age range was 30-69 years. The mean age of ACS Yemeni patients was 56.1 ? 7.7 years, which was less than the mean life expectancy at birth of the Yemeni population (59.8 years).^[30] We only included patients who were younger than 69 years old because there were very few patients over 69 years and the numbers were similar (5 in low altitude and 7 in high altitude). The important finding of this study is that the high-altitude patients were of younger age as compared with the low-altitude patients. The prevalence of hyperlipidemia and previous history of CAD were significantly higher in the high-altitude patients. Past history of diabetes mellitus and smoking was more prevalent with borderline significance. Hemoglobin, hematocrit, and leukocytes were significantly higher in the high-altitude patients. In-hospital complications, such as CVAs, were significantly higher in the high-altitude patients, whereas death and heart failure were slightly higher in the high-altitude patients. Heart rate was significantly higher, whereas the ejection fraction was significantly lower in the high-altitude patients.

The mean age of our patients was lower than the mean age of ACS patients in developed countries, which was 65 years in a European study.^[31] It was also slightly lower than the mean age of developing countries, which was 57 years in Saudi Arabia^[32] and 60 years in Lebanese ACS patients.^[33] Those studies, however, investigated people of heterogeneous ethnicity as a potential confounder not seen in our study, in which all of the patients were Arabs. In the Saudi Arabian study, the researchers included patients of varying ethnic groups, including Arabs, Indians, and Pakistanis. Our patients were also of comparable socioeconomic class -- another potential confounder.

Previous history of CAD was significantly more prevalent in the high-altitude patients. History of CAD is an independent risk factor for ACS. A previous history of diabetes mellitus was slightly more prevalent with borderline significance in patients at higher altitudes. Blood glucose levels were significantly higher among ACS patients at higher altitudes. The overall prevalence of history of diabetes mellitus in ACS patients was 28%. This prevalence was higher than the prevalence of diabetes mellitus in the adult Yemeni population (9.75%).^[34] Our diabetic prevalence was higher than those in developed countries, such as in European ACS patients (23%).^[31] It was also higher than the ACS patients in developing countries, such as Bahrain (22%).^[35] Besides increasing the risk for ACS, diabetes increases the risks for cerebrovascular disease, peripheral vascular disease, and congestive heart failure.^[36]

The prevalence of past history of hypertension among ACS Yemeni patients was comparable at both altitudes, with a mean prevalence of 47.1%. The prevalence of hypertension in the adult Yemeni population is 17.1%.^[34] The in-hospital systolic and diastolic blood pressures were, however, significantly higher in the high-altitude ACS patients in our study. Our prevalence rate of hypertension was comparable to the prevalence of hypertension among ACS patients in developed countries, such as in European ACS patients (48%),^[31] and among ACS patients in developing countries, such as Bahrain (44%).^[35] Hypertension is a strong independent risk factor for the development of cardiovascular disease (CVD) and strongly predicts mortality across populations.^[37] The prevalence of smoking among ACS Yemeni patients at both altitudes was comparable, with a mean prevalence of 61%. An American study provided strong evidence that active smoking is associated with an earlier age of onset of first infarctions, with a striking inverse dose-response effect. Stopping smoking appears to reduce the premature occurrence of coronary events.^[38] Smoking affects atherothrombosis by several mechanisms in addition to accelerating atherosclerotic progression.^[39] Smoking also impairs endothelium-dependent coronary artery vasodilatation besides having multiple adverse hemostatic effects.^[40]

Residence at high altitudes produces physiologic changes for adaptation to long-term hypoxemic conditions.^[41] Adaptive phenomena involve respiratory, cardiovascular,^[42] and hematologic parameters,^[43] which have been shown to vary between people residing in variable altitudes. Hemoglobin was significantly higher among ACS patients at higher altitudes. Our findings agree with the general and expected findings from studies of people living at higher altitudes.^[44,45] The impact of hemoglobin or hematocrit on CVD events appears to differ for different age groups and by sex. Hemoglobin increased with increasing altitude, and it differed between ethnic groups.^[44] An increase in hemoglobin concentration leads to an increased atherosclerotic process. Hematocrit is significantly related to the incidence of CVD, including CAD, myocardial infarction, angina pectoris, and stroke.^[45]

In-hospital complications, especially CVA, were significantly higher among high-altitude patients, and heart failure, death, and arrhythmias showed a higher trend in high-altitude patients. In-hospital complications in high-altitude ACS patients had not been well studied, with a few studies reporting increased rhythm disturbance^[15] and cardiac function abnormalities^[46] in high-altitude individuals. Heart rate in high-altitude ACS patients was significantly higher than in low-altitude patients. High-altitude hypoxia leads to increased heart rate. Although heart rate may be an independent risk factor for sudden CAD death, the associations with other CVD death and nonsudden CAD death appear to be secondary to associations between heart rate and other cardiovascular risk factors.^[47] Another study demonstrated that the heart rate variability is a useful parameter for risk stratification after myocardial infarction. However, the relationship between heart rate itself and its variability has not been adequately researched.^[48] Simple markers, such as peak exercise heart rate and heart rate variability, are powerful predictors of cardiovascular mortality because they are signs of an autonomic nervous system that has been disturbed by the strain of chronic, excessive sympathetic tone.^[49] In-hospital complications were more common in high-altitude patients, which may be due to high-altitude environments, such as increased hemoglobin and hematocrit concentrations (hyperviscosity), as seen in this study. The impact of hematocrit on CVD events appears to differ for different age groups and sex.

In our study, the leukocyte count was significantly higher in high-altitude patients. In men and women of all ages with the spectrum of ACS, the initial leukocyte count is an independent predictor of hospital death and the development of heart failure.^[50] Cardiac wall motion abnormalities detected by echocardiography (hypokinesia, akinesia, and dyskinesia) were slightly more common at higher altitudes than at lower altitudes. The ejection fraction was significantly lower among the high-altitude ACS patients. This may be due to the presence of more necrosis in the myocardium of high-altitude ACS patients. This is supported by the significantly higher levels of cardiac enzymes seen in high-altitude patients.

Conclusion

High-altitude living predisposes Yemenis to CVD, particularly ACS. They develop ACS at a younger age and have a more adverse CVD risk profile. They demonstrate more adverse outcomes, both in terms of investigational findings and clinical events. This suggests that higher altitudes may be a risk factor for ACS and should be taken into account when evaluating cardiovascular risk.

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