Clinical trial NCT05272514: Impact of Hypoxia on Resting and Exertional Right Ventricular Performance
Official title: Impact of Hypoxia on Resting and Exertional Right Ventricular Performance - A PILOT STUDY
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Ventricular Dysfunction, Right
Hypoxia
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
First posted: 2022-03-09
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 10 healthy men and women

Brief summary: The purpose of this study is to better understand how hypoxia (low oxygen) affects resting and exertional right ventricular function in healthy individuals.

Detailed description: The right ventricle plays a critical role in exercise. As workload increases with exercise, the right ventricle augments contractility and lusitropy (diastolic relaxation) to accommodate increased venous return (preload) and pulmonary arterial pressure (afterload). Using gold-standard pressure-volume analysis, the investigators have shown that impairments in right ventricular function limit functional capacity among individuals with cardiovascular disease, heart failure and pulmonary hypertension. In addition, the investigators have characterized right ventricular function during exercise in the healthy heart using these techniques. Hypoxia increases pulmonary arterial pressure via hypoxic pulmonary vasoconstriction. By increasing right ventricular afterload, hypoxia may compromise exercise capacity. However, data regarding the impact of hypoxia on right ventricular performance are lacking.

This is a human physiology study of resting and exertional right ventricular function under control (normoxic) and hypoxic conditions. The investigators will use pressure-volume analysis in conjunction with Swan-Ganz catheterization and echocardiography to assess right ventricular performance in healthy individuals at rest and during exercise in normoxia and hypoxia. The study protocol consists of three visits.

* Visit 1: Non-invasive symptom-limited cardiopulmonary exercise test under normoxic conditions (FiO2= 0.21).
* Visit 2: Non-invasive symptom-limited cardiopulmonary exercise test under hypoxic conditions (FiO2=0.12).
* Visit 3: Invasive resting and exertional hemodynamic assessment under normoxic and hypoxic conditions

In Visits 1 and 2, heart rate/rhythm, oxygen saturation, blood pressure, gas exchange parameters (oxygen uptake \[VO2\], carbon dioxide production \[VCO2\], and minute ventilation), and rated perceived exertion will be monitored. Cardiopulmonary exercise testing (CPET) will be performed on an upright cycle ergometer with workload starting at 0 Watts and increasing every 2 minutes until volitional exhaustion with maximum workload at 8-12 minutes. The order of Visits 1 and 2 will be randomized to reduce the potential for bias from a learning/ordering effect.

In Visit 3, the same non-invasive measurements will be obtained. Additionally, right heart catheterization with Swan-Ganz catheter and conductance catheter placement will be performed. This will provide gold-standard hemodynamic and pressure-volume loop analysis to measure outcomes of right ventricular contractility, lusitropy (diastolic relaxation), afterload, and ventricular-arterial coupling. First, participants will complete submaximal exercise at FiO2=0.21. Submaximal exercise will include 5 minutes at 50% of baseline maximal oxygen uptake (VO2max achieved during Visit 1). After 20 minutes' rest, hemodynamic measurements will be obtained at rest at FiO2 0.21, 0.17, 0.15 and 0.12 to characterize the impact of progressive hypoxia on resting right ventricular hemodynamics. Participants will then perform submaximal exercise (50% VO2 max from hypoxic baseline at Visit 2) at FiO2 0.12. Thereafter, participants will complete a symptom-limited CPET at FiO2 0.12 with monitoring of invasive hemodynamics.

Eligibility criteria: Inclusion Criteria:

* Age 18 - 60
* For women, premenopausal status

Exclusion Criteria:

* Active cardiovascular or pulmonary disease (e.g. hypertension, coronary artery disease, cardiomyopathy, arrhythmia, valvular abnormalities, diabetes, peripheral vascular disease, tobacco use, chronic obstructive pulmonary disease, asthma, interstitial lung disease, restrictive lung disease, or pulmonary hypertension)
* Use of cardiac- or pulmonary-related medications
* Prior history of high altitude pulmonary edema or high altitude cerebral edema
* Body mass index \< 18.5 or \> 30
* Anemia
* Iron deficiency
* Iron supplementation (oral or intravenous) in the preceding 60 days
* Systemic anticoagulation or aspirin use that cannot be temporarily held for the study
* Pregnancy
* Non-cardiopulmonary disorders that adversely influence exercise ability (e.g. arthritis or peripheral vascular disease)
* Dedicated athletic training (defined here as spending \>9 hours per week in vigorous physical activity \[≥6 mets\])
* Regular high-altitude exercise (defined here as engaging in vigorous physical activity \[≥1 hour at ≥6 mets\] at ≥8,000 ft for \>2 days per week over the preceding 4 weeks)
* Residence at ≥8,000 ft for 3 or more consecutive nights in the preceding 30 days

Primary outcomes:
measure: Right ventricular contractility measured by conductance catheter
timeFrame: Up to 1 hour
measure: Right ventricular lusitropy (diastolic function) measured by conductance catheter
timeFrame: Up to 1 hour
Secondary outcomes:
measure: Right ventricular stroke work measured by conductance catheter
timeFrame: Up to 1 hour
measure: Mean pulmonary artery pressure measured by right heart catheterization
timeFrame: Up to 1 hour
measure: Cardiac output derived from right heart catheterization
timeFrame: Up to 1 hour
measure: Workload
timeFrame: Up to 1 hour
measure: Maximal oxygen uptake
timeFrame: Up to 1 hour
measure: Plasma acylcarnitine 10:0 measured by peripheral venous metabolomics (ultra-high performance liquid chromatography coupled to mass spectrometry)
timeFrame: Up to 1 hour
measure: Red blood cell acylcarnitine 10:0 measured by peripheral venous metabolomics (ultra-high performance liquid chromatography coupled to mass spectrometry)
timeFrame: Up to 1 hour
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
Study officials:
References:
citation: Smith TG, Balanos GM, Croft QP, Talbot NP, Dorrington KL, Ratcliffe PJ, Robbins PA. The increase in pulmonary arterial pressure caused by hypoxia depends on iron status. J Physiol. 2008 Dec 15;586(24):5999-6005. doi: 10.1113/jphysiol.2008.160960. Epub 2008 Oct 27.
citation: Smith TG, Talbot NP, Privat C, Rivera-Ch M, Nickol AH, Ratcliffe PJ, Dorrington KL, Leon-Velarde F, Robbins PA. Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials. JAMA. 2009 Oct 7;302(13):1444-50. doi: 10.1001/jama.2009.1404.
citation: Cornwell WK, Tran T, Cerbin L, Coe G, Muralidhar A, Hunter K, Altman N, Ambardekar AV, Tompkins C, Zipse M, Schulte M, O'Gean K, Ostertag M, Hoffman J, Pal JD, Lawley JS, Levine BD, Wolfel E, Kohrt WM, Buttrick P. New insights into resting and exertional right ventricular performance in the healthy heart through real-time pressure-volume analysis. J Physiol. 2020 Jul;598(13):2575-2587. doi: 10.1113/JP279759. Epub 2020 May 18.
citation: Cornwell WK 3rd, Baggish AL, Bhatta YKD, Brosnan MJ, Dehnert C, Guseh JS, Hammer D, Levine BD, Parati G, Wolfel EE; American Heart Association Exercise, Cardiac Rehabilitation, and Secondary Prevention Committee of the Council on Clinical Cardiology; and Council on Arteriosclerosis, Thrombosis and Vascular Biology. Clinical Implications for Exercise at Altitude Among Individuals With Cardiovascular Disease: A Scientific Statement From the American Heart Association. J Am Heart Assoc. 2021 Oct 5;10(19):e023225. doi: 10.1161/JAHA.121.023225. Epub 2021 Sep 9.