Influence of altitude on hypertension phenotypes and responses to antihypertensive therapy: Review of the literature and design of the INTERVENCION trial

Abstract

Systemic arterial hypertension constitutes the leading cause of mortality worldwide, and affects people living at different altitudes above sea level (AASL). AASL has a major impact on cardiovascular function and various biologic pathways that regulate blood pressure–related phenotypes, but whether it affects the clinical response to antihypertensive therapy is unknown. The hemodynamic adaptations observed among lowlanders acutely exposed to high altitude (HA) is distinct from those observed among HA dwellers. However, the phenotypic patterns of hypertension and the response to standard antihypertensive agents among adults chronically exposed to different AASL are poorly understood. The authors describe the protocol for the INTERVENCION trial, a randomized clinical trial designed to assess the effects of three first‐line antihypertensive monotherapies (a thiazide diuretic, an angiotensin receptor blocker, and a calcium channel blocker) on peripheral and central blood pressure, in‐office blood pressure, and ambulatory blood pressure hemodynamics of hypertensive patients living at different AASL (low altitude, intermediate altitude, and high altitude). The primary end point is the reduction in 24‐hour brachial systolic blood pressure. The INTERVENCION trial will provide the first clinical trial data regarding the influence of AASL on the response to antihypertensive monotherapy, as well as the hemodynamic characteristics of arterial hypertension at different AASL.

1. INTRODUCTION

Over the last century, developed countries have faced an epidemic of cardiovascular disease (CVD). ¹ This led to the implementation of risk factor control and treatment strategies translating into a decrease in CVD morbidity and mortality at the end of the 20th century. ² It has been widely demonstrated that elevated blood pressure (BP) and its consequences constitute the major cause of death worldwide, since it is the most important risk factor for cerebrovascular and coronary events. ³ BP can be affected by various individual determinants, such as diet and sodium intake, body mass index, and age, among others. ⁴ In addition, there is increasing recognition of the effects of environmental factors on blood pressure, including ambient temperature and altitude above sea level (AASL), among others. ⁵

Hypertension is considered a major global public health issue, and the high burden of hypertension in developing countries is increasingly being recognized. ⁶ The World Hypertension League has made important efforts to address the current extent of hypertension worldwide by raising awareness of the effects of hypertension in low‐ and middle‐income countries where the majority of high‐altitude (HA) locations are, addressing the effects of dietary salt consumption on BP, and developing hypertension prevalence estimator tools, which constitute relevant approaches to lower hypertension morbidity and mortality. ⁷ , ⁸ , ⁹ , ¹⁰ Approximately 83 million people live at HA, classically defined as >2500 meters above sea level (mASL; ~8200 ft). ¹¹ Noncommunicable diseases, including hypertension, exhibit higher prevalence in low‐income countries, such as the majority of highlanders. Nonetheless, the real burden of hypertension at HA remains unknown. ¹¹

1.1. Effects of AASL on blood pressure

HA constitutes a special environment, in which lower atmospheric pressures determine a lower driving pressure for gas exchange in the lungs, leading to lower partial pressure of oxygen in the alveoli. ¹¹ A clear distinction must be made between the mechanisms, phenotypic patterns, and response to therapy in HA chronic dwellers as compared to lowlanders acutely exposed to HA. In contrast to the large number of studies focused on the cardiovascular consequences of acute exposure to HA among lowlanders, the impact of chronic exposure to HA on phenotypic patterns of hypertension and cardiovascular disease is less well understood.

Hemodynamic changes of lowlanders acutely exposed to HA are characterized by elevation of BP due to higher peripheral vascular resistance, endothelial dysfunction, and augmented oxidative stress. ¹² , ¹³ These changes appear to be mediated mainly by an acute hyperadrenergic state triggered to overcome the acute cerebral arterial dysregulation observed during acute HA exposure, in order to maintain proper brain oxygenation. ¹⁴ , ¹⁵ , ¹⁶ Upregulation of endothelin receptors in the heart and aorta may also contribute to this response. ¹⁷ , ¹⁸ Synthesis of erythropoietin is induced during acute HA exposure, and it contributes to the acute elevation in BP as it enhances the hyperadrenergic response via increasing sensitivity to endogenous catecholamines, and increases release and activation of endothelin receptors. ¹⁹ , ²⁰ The renin‐angiotensin‐aldosterone system (RAAS) is suppressed during acute exposure to HA, and does not play a major role in this response. ²¹

Chronic exposure to HA can trigger an exaggerated response to chronic hypoxemia characterized by a marked production of red blood cells, persistent hypoxic pulmonary vasoconstriction leading to pulmonary arterial hypertension, and the development of right‐sided heart failure. This syndrome is known as chronic mountain disease, which is mainly displayed by Andean highlanders. ²² On the other hand, Tibetan highlanders exhibit a response characterized by higher systemic BP, and therefore higher incidence of systemic hypertension, as an attempt to increase cerebral blood flow to maintain optimal cerebral perfusion and oxygen delivery. ¹⁴ , ²³ , ²⁴ , ²⁵

1.2. Effects of antihypertensive treatment at intermediate and high AASL

Despite the large number of hypertensive people living at intermediate or high AASL, the effect of AASL on the response to standard antihypertensive agents is largely unknown. Only one trial that assessed the antihypertensive efficacy of different agents among 142 hypertensive patients living at three different altitudes (100 mASL or ~330 ft, 1538 mASL or ~5000 ft, and 2600 mASL or ~8500 ft) showed that valsartan and enalapril were equally efficacious at lowering BP after 4 weeks. ²⁶ However, both these agents work on the RAAS, and to the best of our knowledge, no randomized trial has systematically compared the efficacy of antihypertensive agents from the three major antihypertensive drug classes used as first‐line therapy, at different AASL. Moreover, no data are available regarding the patterns of central hemodynamics, large artery stiffness, ambulatory brachial and central blood pressure, and the changes of these important parameters in response to antihypertensive therapy at different AASL.

2. DESIGN OF THE INTERVENCION TRIAL

The INTERVENCION trial was designed to: (a) evaluate the peripheral and central 24‐hour BP reduction in response to first‐line antihypertensive therapy with the following agents: a thiazide diuretic (hydrochlorothiazide), an angiotensin II receptor blocker (telmisartan), and a calcium channel blocker (amlodipine), in mild hypertension, at low AASL (<1500 mASL, ~5000 ft), intermediate AASL (1500‐3000 mASL; 5000‐10 000 ft), and high AASL (>3000 mASL; >~10 000 ft); (b) determine whether differences exist regarding the response to different antihypertensive medications according to the AASL; and (c) evaluate office and ambulatory hemodynamic patterns in hypertensive patients living at low, intermediate, and high AASL.

2.1. Study population and sample size

The INTERVENCION trial is a prospective, randomized, multicenter, open‐label trial. Untreated hypertensive patients living at low, intermediate, and high AASL were enrolled across sites listed in Table 1. Enrollment was stratified by age, sex, and AASL, to assure a balanced sex and age distribution at different AASL. Inclusion and exclusion criteria are listed in Table 2. Briefly, inclusion criteria were as follows: age between 45 and 75 years; a minimum period of residence of 2 years in the cities where the participants are enrolled; and untreated stage 1 or mild arterial hypertension determined by office BP readings (SBP, systolic blood pressure between 140 and 159 mm Hg and/or diastolic BP of 90 to 99 mm Hg, without treatment). Exclusion criteria include the following: diabetes mellitus; chronic kidney disease; smoking; pulmonary, liver, or neoplastic disease; presence of any factor that might alter short‐term survival; psychiatric disease; cardiac disease; cerebrovascular accident; orthostatic hypotension; syncope; allergy of history of side effects with prior use of calcium channel blocker, thiazide diuretics, or angiotensin II receptor blockers; and inability to provide informed consent.

TABLE 1.

INTERVENCION Study Centers

	Location	AASL
Low AASL: <1500 mASL (<~5000 ft)
Camana Hospital	Camana, AQP, Peru	15 mASL (49 ft)
Alto Inclan Health Center	Mollendo, AQP, Peru	27 mASL (89 ft)
Vitor Health Center	Vitor, AQP, Peru	1244 mASL (4081 ft)
Intermediate AASL: 1500‐3000 mASL (~5000‐10 000 ft)
PREVENCION Research Institute	Cayma, AQP, Peru	2403 mASL (7884 ft)
Maritza Campos Diaz Health Center	Cerro Colorado, AQP, Peru	2419 mASL (7936 ft)
Francisco Bolognesi Health Center	Cayma, AQP, Peru	2420 mASL (7940 ft)
High AASL: >3000 mASL (>~10 000 ft)
Ichupampa Health Center	Caylloma, AQP, Peru	3397 mASL (11 145 ft)
Coporaque Health Center	Caylloma, AQP, Peru	3583 mASL (11 755 ft)

Abbreviations: AASL, altitude above sea level; AQP, Arequipa.

TABLE 2.

Inclusion and exclusion criteria of the INTERVENCION trial

Inclusion criteria

Age 45‐75 y Living in the enrollment cities for at least 2 y Untreated hypertension for at least 2 wk Systolic BP between 140 and 160 mm Hg and/or diastolic BP between 90 and 99 mm Hg, in the absence of therapy

Exclusion criteria

Diabetes mellitus Chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2 of body surface area) Smoking Lung disease, liver disease, or active cancer Any factor that, in the opinion of the investigator, decreases short‐term survival Psychiatric illness Inability to provide informed consent Heart disease (myocardial infarction, heart failure, valvular heart disease, cardiomyopathy, atrial fibrillation, or any significant cardiac arrhythmia) Cerebrovascular disease Orthostatic hypotension History of syncope History of allergy or adverse effects to study medications or drugs of the same pharmacologic classes

A target sample size of 160‐170 participants was estimated to achieve complete data and follow‐up evaluations in 150 participants. A sample of 150 participants completing the trial provides 85% power to detect a group difference of at least 2.75 mm Hg, assuming a 10‐mm Hg standard deviation of the primary end point (24‐hour SBP reduction), at an α level of .05. A computer‐generated list was utilized for stratified and block randomization according to altitude, sex, and age group (45‐60 years and 61‐75 years), in a 1:1:1 ratio to hydrochlorothiazide (25 mg daily), telmisartan (80 mg daily), and amlodipine (10 mg daily), which were administered orally between 6 am and 8 am, for 4 weeks. Initiation of agents belonging to one of these therapeutic groups is consistent with current guidelines. ²⁷ , ²⁸ An intervention period of 4 weeks was selected, given the difference between antihypertensive efficacy at 4 weeks as compared to longer periods weeks is small, and this is in agreement with clinical practice. ²⁷ , ²⁸ , ²⁹

2.2. Study end points

The primary end point is the reduction in 24‐hour brachial SBP. Secondary end points of the trial include the following: (a) proportion of patients with controlled BP (office and 24‐hour BP measurement); (b) change in 24‐hour diastolic, mean, and pulse BP; (c) change in central (aortic) pulse pressure, measured with carotid arterial tonometry, and measured with radial arterial tonometry using a generalized transfer function to estimate aortic pressure; (d) change in the magnitude of wave reflections; and (e) change in carotid‐femoral pulse wave velocity (a measure of large artery stiffness) and carotid‐radial pulse wave velocity (a measure of muscular artery stiffness). ³⁰ , ³¹

2.3. Study procedures and ancillary studies

The study participant flowchart and general design is represented in Figure 1. During the initial visit, a thorough medical history and physical examination was performed. Participants underwent a 12‐lead electrocardiogram and basic laboratory assessments to assess eligibility. In‐office BP measurements were obtained according to the JNC‐7 recommendations, using a validated oscillometric device (Omron 705IT; HEM‐759‐E). ³² , ³³ ABPM (ambulatory BP monitoring) was performed using Mobil‐O‐Graph devices (APC Cardiovascular), capable of monitoring pulse wave analysis (PWA) using the oscillometric method, allowing for the study of central SBP and other central hemodynamic parameters over a 24‐hour period. ³⁴ In‐office noninvasive measurements of central and peripheral hemodynamic parameters were obtained via arterial applanation tonometry, using a commercially available system (SphygmoCor, AtCor Medical) that uses a high‐fidelity applanation tonometer (Millar Instruments). The tonometer was used to record carotid and radial pressure waveforms. Radial diastolic and mean pressures were used to calibrate the carotid pressure waveform.

FIGURE 1.

General study design and flowchart of participants

Carotid‐femoral pulse wave velocity (PWV) (SphygmoCor, AtCor Medical) measurements were obtained with sequential tonometric recordings of the carotid and femoral pulse, using the QRS complex as a fiducial time point. CF‐PWV, a marker of central vascular (aortic) stiffness, is a strong predictor of future cardiovascular events and all‐cause mortality in various populations, ³⁵ and is a strong predictor of cardiovascular risk in hypertensive patients. ³⁶ Carotid‐radial pulse wave velocity was assessed in an analogous manner, with sequential tonometric recordings of the carotid and radial pulse, using the QRS complex as a fiducial time point. Arterial tonometry was also used to perform carotid and radial PWA. Radial PWA allows the assessment of peripheral pressure waveforms, which generates the corresponding aortic waveform via the generalized transfer function of the Sphygmocor device. Key parameters assessed from radial tonometric recordings include the peripheral and central augmentation index, central pulse pressure, central SBP, and indices of wave reflection based on wave separation of the central pressure waveform using physiologic flow waveform approaches. ³⁷ , ³⁸ Similar analyses will be performed using the carotid pressure waveform, which is a direct surrogate of the aortic pressure waveform and does not rely of the application of a generalized transfer function.

Physical activity was evaluated using the short version of the International Physical Activity Questionnaire (IPAQ). ³⁹ Dietary habits were assessed using the MEDFICTS questionnaire, a brief dietary assessment instrument freely provided by the NCEP (National Cholesterol Education Program) ATP (Adult Treatment Panel) guidelines. ⁴⁰ Symptoms of anxiety or depression, which have been identified as important predictors of cardiovascular events, ⁴¹ , ⁴² will be assessed using the HADS (Hospital Anxiety and Depression Scale) questionnaire. ⁴³ Blood samples were banked for various biomarker studies. Plasma and serum samples are stored at −80°C for future circulating biomarker analyses.

2.4. Regulatory aspects and sponsorship

The trial protocol was approved by the Ethics Committee and Institutional Review Board of Carlos Alberto Seguin Escobedo National Hospital EsSALUD, Arequipa, Peru. The study was sponsored by the Santa Maria Catholic University of Arequipa, and the Peruvian Society of Cardiology. The trial is registered at ClinicalTrials.gov with trial ID NCT02373163. Farmindustria (Lima, Peru) provided the study medications at no cost. AtCor Medical provided Sphygmocor PVx devices for the trial at no cost.

3. CONCLUSIONS

AASL is a key regulator of cardiovascular function and likely impacts the phenotypic patterns of hypertension and the response to antihypertensive therapy. Whereas much is known about the short‐term cardiovascular effects of altitude, data are scarce about the differences in the hemodynamic patterns of hypertension between populations living at low, intermediate, and high AASL. More importantly, a key knowledge gap exists regarding the efficacy of first‐line antihypertensive agents at different AASL. Findings from this trial will advance our understanding of the role of AASL on hypertensive phenotypes and response to therapy.

CONFLICT OF INTEREST

JAC is supported by NIH grants R01‐HL 121510‐01A1, R61‐HL‐146390, R01‐AG058969, 1R01‐HL104106, P01‐HL094307, R03‐HL146874‐01, and R56‐HL136730. He has received consulting honoraria from Sanifit, Microsoft, Fukuda‐Denshi, Bristol‐Myers Squibb, OPKO Healthcare, Ironwood Pharmaceuticals, Pfizer, Akros Pharma, Merck, Edwards Lifesciences, Bayer, and JNJ. He has received research grants from the NIH, Microsoft, Fukuda‐Denshi, and Bristol‐Myers Squibb and device loans from Atcor Medical, Fukuda‐Denshi, and Microvision. He is named as inventor in an UPenn patent for the use of inorganic nitrates/nitrites for the treatment of HF and preserved ejection fraction and a patent application for the use of novel neoepitope biomarkers of tissue fibrosis in heart failure. Other authors have no disclosures.

AUTHOR CONTRIBUTIONS

Josefina Medina‐Lezama (JML) is the principal investigator of the study and contributed to the conceptualization and design of the trial. Karela Herrera‐Enriquez (KHE) and Offdan Narvaez‐Guerra (ONG) wrote the first draft. Julio A. Chirinos (JAC) is the corresponding author and contributed to the trial design, interpretation and writing. All authors contributed to critical revision and approved the manuscript.

Medina‐Lezama J, Herrera‐Enriquez K, Narvaez‐Guerra O, Chirinos JA. Influence of altitude on hypertension phenotypes and responses to antihypertensive therapy: Review of the literature and design of the INTERVENCION trial. J Clin Hypertens. 2020;22:1757–1762. 10.1111/jch.13932