Kynurenine/Tryptophan Ratio in Hypertension Associated to Obstructive Sleep Apnea (KYNTOSA)

Relevance of the Ratio Kynurenine/Tryptophan to Characterize Hypertension Associated to Obstructive Sleep Apnea (KYNTOSA)

Obstructive Sleep Apnea (OSA) is an independent risk factor for hypertension (HTN) and the most common cause of resistant HTN. The mechanisms underlying OSA-associated HTN are not completely understood. This is crucial to find novel therapeutic targets of OSA-associated HTN. The Aryl Hydrocarbon Receptor (AHR) is a cytosolic transcription factor that has been linked with the pathogenesis of HTN.

This study aims to evaluate the role of endogenous ligands of AHR such as kynurenine in discriminating patients with OSA-associated HTN. For that aim, a case-control study will be performed in patients with and without hypertension exposed and not exposed to OSA. Kynurenine and other metabolites will be quantified in urine and serum samples.

Study Overview

• Status: Active, not recruiting
• Conditions: Hypertension Secondary

• Study Type: Observational
• Enrollment (Actual): 203

Contacts and Locations

Study Locations

• Portugal
  • Lisboa, Portugal
    • Hospital da Luz
  • Lisboa, Portugal
    • Centro Hospitalar de Lisboa Central
  • Lisboa, Portugal
    • Hospital Fernando Fonseca
  • Lisboa, Portugal
    • Hospital Beatriz Angelo
  • Lisboa, Portugal
    • Centro Hospitalar Lisboa Ocidental

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

The study population will include 4 groups of adults: healthy volunteers; normotensive OSA patients; hypertensive OSA patients; hypertensive non OSA patients.

Description

CASES (subjects with hypertension with and without OSA)

Inclusion Criteria:

• Adults ≥ 30 years old attending the outpatient clinics of the clinical sites.
• Diagnosis of hypertension defined either as: a) use of antihypertensive drug(s) and stable dose for at least 2 weeks prior to inclusion; or b) in untreated patients: office systolic blood pressure values >= 140 mmHg and/ or diastolic blood pressure values >= 90 mmHg.
• Able to understand and communicate effectively with study personnel.
• Giving written informed consent to participate.

Exclusion Criteria:

• Self-reported pregnancy or breastfeeding.
• Patients on haemodialysis or peritoneal dialysis.
• Chronic liver disease with Child-Pugh score B or higher.
• Hypertension attributed to renal artery stenosis, primary hyperaldosteronism, pheochromocytoma, Cushing's syndrome, coarctation of aorta.
• History of any OSA surgical treatment to the palatal and hypopharyngeal regions, notably uvulopalatopharyngoplasty surgery (UPPP), palatal radio frequency ablation, tonsillectomy, lingual tonsillectomy, partial glossectomy, tongue base radio frequency ablation, genioglossal advancement, hyoid suspension, maxillomandibular advancement surgery (MMA) and active use of hypoglossal nerve stimulator.
• Patients with a good adherence to CPAP, defined as the use of CPAP for at least 4 hours/night on 70% of nights during the last 3 months.
• Pulmonary hypertension.
• Current diagnosed oncological disease.
• Patients with known chronic or acute infectious diseases.
• Other current severe progressive or uncontrolled disease which in the judgement of the investigator renders the patient unsuitable for the study

CONTROLS (individuals without hypertension with and without OSA) For each case, an age and gender-matched control will be selected.

Exclusion Criteria:

• Pregnancy or breastfeeding.
• Patients on haemodialysis or peritoneal dialysis.
• Chronic liver disease with Child-Pugh score b or higher.
• History of any OSA surgical treatment to the palatal and hypopharyngeal regions, notably uvulopalatopharyngoplasty surgery (UPPP), palatal radio frequency ablation, tonsillectomy, lingual tonsillectomy, partial glossectomy, tongue base radio frequency ablation, genioglossal advancement, hyoid suspension, maxillomandibular advancement surgery (MMA) and active use of hypoglossal nerve stimulator.
• Patients with a good adherence to CPAP, defined as the use of CPAP for at least 4 hours/night on 70% of nights during the last 3 months.
• Pulmonary hypertension.
• Current diagnosed oncological disease.
• Patients with known chronic or acute infectious diseases.
• Patients with known chronic or acute infectious diseases.
• Other current severe progressive or uncontrolled disease which in the judgement of the investigator renders the patient unsuitable for the study.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
HTN_OSA; Patients with hypertension* with obstructive sleep apnea** * Hypertension will be defined as: i) use of antihypertensive drug(s) and stable dose for at least 2 weeks prior to inclusion; or ii) in untreated patients: office systolic blood pressure values >= 140 mmHg and/ or diastolic blood pressure values >= 90 mmHg. ** OSA will be defined with a polysomnography level 1, 2 or 3 performed within the previous twelve months with: an apnea-hypopnea index > 5 events per hour (with more than 50% of obstructive events) associated with symptoms (associated sleepiness, fatigue, insomnia, snoring, subjective nocturnal respiratory disturbance or observed apnea) or medical/psychiatric disorder (hypertension, coronary artery disease, atrial fibrillation, congestive heart failure, stroke, diabetes, cognitive dysfunction, or mood disorder), OR; an apnea-hypopnea index > 15 events per hour, AND; no significant changes in health, medications, or lifestyle since the polysomnography.
HTN_NoOSA; Patients with hypertension without obstructive sleep apnea
NoHTN_OSA; Patients without hypertension with obstructive sleep apnea
NoHTN_NoOSA; Patients without hypertension without obstructive sleep apnea (healthy controls)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Kynurenine / Tryptophan ratio	Ratio between kynurenine and tryptophan concentrations	Day 1 (visit 1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentrations of metabolites	The relevant metabolites and their concentration will be identified by Partial Least Square Discriminant Analysis (PLS-DA) applied to non-targeted metabolomics.	Day 1 (visit 1)

Collaborators and Investigators

• Sponsor: Universidade Nova de Lisboa
• Collaborators: Hospital da Luz, Portugal; Centro Hospitalar Lisboa Ocidental; Centro Hospitalar de Lisboa Central; Hospital Beatriz Ângelo; Hospital Fernando Fonseca
• Investigators: Principal Investigator: Maria E Monteiro, PhD, Universidade NOVA Lisboa

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2021
• Primary Completion (Actual): September 1, 2023
• Study Completion (Estimated): March 1, 2024

Study Registration Dates

• First Submitted: October 12, 2020
• First Submitted That Met QC Criteria: November 20, 2020
• First Posted (Actual): November 30, 2020

Study Record Updates

• Last Update Posted (Estimated): December 7, 2023
• Last Update Submitted That Met QC Criteria: December 6, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: hypertension; obstructive sleep apnea; tryptophan; aryl hydrocarbon receptor
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Hypertension
• Other Study ID Numbers: Kyntosa_02_20200428; PTDC/MED-TOX30418/2017 (Other Grant/Funding Number: Fundação para a Ciência e a Tecnologia)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No