Mechanisms of Pulmonary Vascular Dysfunction in Heart Failure

Study Purpose

Heart failure (HF) patients often develop pulmonary hypertension (PH) that leads to transition into a biventricular HF with poor prognosis. There are two PH components: 1) passive transmission of increased left atrial pressure, 2) heart failure (HF) related pulmonary vascular dysfunction (PVD) with increased vascular resistance. Intriguingly, only some, but not all HF patients develop heart failure-related PVD. The mechanisms and non-invasive detection of HF-PVD are poorly understood and are the focus of the current grant application. Development of PVD is linked to insufficiently characterized metabolic factors that may be mediators of HF-PVD. Untargeted metabolomics is an emerging powerful platform for the discovery of pathways linked to diseases. Its specificity can be further enhanced using transpulmonary gradient sampling. Part A of the project aims to identify novel metabolites associated with the presence of PVD in patients with HF that can serve as biomarkers or targets and will provide biologic insights into PVD. Part C will assess the effects of reverting of metabolic alterations (identified in part A) by a drug/diet on pulmonary vasculature in experimental HF-related PVD. The "gold standard" for the detection of PVD is right heart catheterization, which is invasive and risky. Heart failure-related PVD is therefore often diagnosed late. There is a need for noninvasive tests that may help to detect PVD in early stages and can be done repeatedly. Recent advances in artificial intelligence (AI)-assisted automated quantitative analysis of lung texture from low-dose contrast-free high-resolution CT images allow to quantify lung water content, interstitial changes or vessel volume, and may provide clues for detection of heart failure-related PVD. Such an approach, not tested yet, will be utilized for the detection of HF-PVD (part B). Clinical and functional characteristics of lung circulation (exercise hemodynamics, diffusion capacity, perfusion) will be analyzed in relation to quantitative CT data.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Observational
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion Criteria

A) Inclusion Criteria. HF group:

- age>18y.

- signed informed consent, - left ventricular (LV) ejection fraction <50% - duration of HF>6 months, - loop diuretic use, - clinical indication to right heart catheterisation.

Control group:

- Age >18years.

- Signed informed consent.

- Non-HF subjects referred to Institute for Clinical and Experimental Medicine (IKEM) in Prague for an invasive procedure (PFO closure, arrhythmia ablation, for subjects undergoing RHC) or non-invasive diagnostic evaluation (controls without invasive sampling) B)
Exclusion Criteria:
Heart Failure group: - Patients with hemodynamic instability requiring inotropic support.

- Severe renal insufficiency (estimated glomerular filtration rate <0.6 ml/s) - Acute coronary syndrome.

- High cardiac output (cardiac index >4 l/m2) - Known pulmonary hypertension of other type than II (type I, III, IV) - Active infection.

- Respiration insufficiency.

- Large pleural effusion.

- Severe intrinsic lung disease (treated chronic obstructive pulmonary disease (COPD) - asthma, known interstitial lung disease) Control group: - Pulmonary hypertension (RV systolic pressure estimate on screening > 45 mmHg) - History of recent pulmonary embolism < 1 year.

- Echocardiographic evidence of reduced function of right or left ventricle.

- Treated asthma/COPD, known intersticial lung disease.

- Significant exercise intolerance (NYHA > II)

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06331208
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Institute for Clinical and Experimental Medicine
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Vojtech Melenovsky
Principal Investigator Affiliation	Institute for Clinical and Experimental Medicine
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Not yet recruiting
Countries	Czechia
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Heart Failure, Pulmonary Hypertension, Pulmonary Vascular Resistance Abnormality

Additional Details

Goals of the project are: A) To identify metabolic factors associated with the development of heart failure related pulmonary vascular disease (PVD) using unbiased metabolomic analysis of blood samples obtained before and after passage through lungs (transpulmonary metabolome), obtained during medically indicated right heart catheterization of HF patients with variable degree of pulmonary vasculopathy. Findings from discovery cohort A1 (200 HF, 30 controls) will be prospectively validated in validation cohort A2 (200 HF, 30 controls). Clinical data (medication, comorbidities, nutritional intake) will be analyzed to identify explanatory links to transpulmonary metabolome and increased pulmonary vascular resistance. The goal is to discover metabolic factors and pathways critical for PVD development, that might be targeted by pharmaco-intervention. B) To identify structural and functional characteristics of heart failure (HF) related PVD using advanced imaging (cohort B, 60 HF patients, 30 controls). Advanced non-invasive imaging methods (high resolution non-contrast CT, SPECT) will be used to identify early changes in lung structure indicating the presence of pulmonary vascular disease. HF subjects with variable elevation of pulmonary vascular resistance will be extensively phenotyped using novel automated AI-augmented analysis of CT data texture, and by SPECT perfusion imaging. These morphologic characteristics will be linked to functional parameters (diffusion capacity, pulmonary vascular resistance change during exercise). The goal is to develop non-invasive imaging markers of early PVD due to HF. C) To test the impact of the correction of metabolic abnormalities on heart failure-related PVD in animal model. Animal model mimicking PVD due to HF will be characterized and the impact of the dietary or pharmacological intervention (based on findings from part A) on pulmonary hemodynamics will be tested in rats with myocardial infarction by left anterior descending (LAD) artery ligation combined with low-dose toxin to pulmonary circulation (monocrotaline or substance Sugen 5416).

Arms & Interventions

Arms

: controls

Subjects without heart failure or pulmonary hypertension undergoing clinically indicated diagnostic evaluation or therapeutic procedure

: heart failure

Subjects with chronic heart failure due to reduced ejection fraction (EF), undergoing clinically indicated right heart catheterisation (evaluation for left ventricular assist device (LVAD)/transplantation (TX) or other decision)

Interventions

Diagnostic Test: - non-contrast chest CT

patients who undergo clinically indicated evaluation of pulmonary circulation (right heart catheterisation - RHC) will undergo non-contrast CT of the chest, blood sampling from pulmonary artery and spirometry with DLCO analysis.

Diagnostic Test: - spirometry with diffusing lung capacity for carbon monoxide (DLCO) analysis

patients who undergo clinically indicated evaluation of pulmonary circulation (RHC) will undergo non-contrast CT of the chest, blood sampling from pulmonary artery and spirometry with DLCO analysis.

Diagnostic Test: - Omics analysis of blood plasma obtained from pulmonary artery or peripheral blood

patients who undergo clinically indicated evaluation of pulmonary circulation (RHC) will undergo non-contrast CT of the chest, blood sampling from pulmonary artery and spirometry with DLCO analysis.

Diagnostic Test: - supine bike exercise during right heart catheterisation

subgroup of HF subjects who undergo right heart catheterisation will perform short supine bike exercise during RHC

Diagnostic Test: - Lung ventilation/perfusion SPECT

subgroup of HF subjects will undergo ventilation/perfusion SPECT

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