The Right Ventricle in Chronic Pressure Overload: Identifying Novel Molecular Targets for Functional Imaging

Study Overview
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Brief Summary
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Chronically elevated pulmonary pressures do not immediately result in right ventricular failure. During the initial period of exposure, the RV adapts to the increased afterload by altering its metabolism and morphology so as to meet the increased work requirement. Several, interconnected adaptive mechanisms have been proposed, including myocyte hypertrophy, a switch in the primary fuel used for ATP generation, increased angiogenesis, and decreased production of mitochondrial reactive oxygen species. While adaptation is initially successful in many cases, it is temporary, and after an uncertain period of time, the ventricle begins to fail. This transition from a compensated to decompensated state is difficult to predict clinically, and patients with different etiologies of CPOS progress to overt RV failure over significantly different time periods. This variability hinders the implementation of treatments that are tailored to a specific disease stage.

Detailed Description
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Chronically elevated pulmonary pressures do not immediately result in right ventricular failure. During the initial period of exposure, the RV adapts to the increased afterload by altering its metabolism and morphology so as to meet the increased work requirement. Several, interconnected adaptive mechanisms have been proposed, including myocyte hypertrophy, a switch in the primary fuel used for ATP generation, increased angiogenesis, and decreased production of mitochondrial reactive oxygen species. While adaptation is initially successful in many cases, it is temporary, and after an uncertain period of time, the ventricle begins to fail. This transition from a compensated to decompensated state is difficult to predict clinically, and patients with different etiologies of CPOS progress to overt RV failure over significantly different time periods. This variability hinders the implementation of treatments that are tailored to a specific disease stage. As right heart failure is the primary outcome determinant in patients with pulmonary hypertension, understanding the major mediators of RV compensation, failure and recovery is essential to improving patient survival. Recently, there have been significant advances in the ability to assess RV function in vivo using functional imaging techniques, including positron emission tomography (PET) and cardiac MRI (CMR). CMR is an established and validated method of precisely defining cardiac structure and function, and new PET protocols have been developed that measure glucose utilization, oxygen consumption, apoptosis and angiogenesis. Importantly, the in vivo nature of PET and CMR allow for the non-invasive collection of detailed structural, metabolic and physiologic data on the performance of the RV5. When taken in combination with established echocardiographic evaluation, these new platforms allow in-depth analysis of cardiac structure and function without the need for invasive procedures. In order to maximize the potential of these techniques, however, a molecular imaging target needs to be identified so as to allow physicians to detect the transition from a compensated to decompensated state. Such a marker has not yet been reported

Official Title
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The Right Ventricle in Chronic Pressure Overload: Identifying Novel Molecular Targets for Functional Imaging

Conditions
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Chronic Thromboembolic Pulmonary Hypertension

Intervention / Treatment
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* Procedure: Right ventricular biopsies


Participation Criteria
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Eligibility Criteria
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-Inclusion Criteria: Chronic thromboembolic pulmonary hypertension group: Patients undergoing pulmonary endarterectomy at Marie Lannelongue Surgical Center for the treatment of chronic thromboembolic pulmonary hypertension. Control group: Patients undergoing adult cardiac surgery without evidence of pulmonary hypertension on preoperative assessment Exclusion Criteria: Chronic thromboembolic pulmonary hypertension group: Insufficient biopsy material, pre-operative therapy with bosentan or sildenafil Control group: Insufficient biopsy sample, ischemic cardiomyopathy, miral or tricuspid valve disease, pre-operative pulmonary hypertension.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CTEPH<br>Patients undergoing pulmonary endarterectomy for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). | Procedure: Right ventricular biopsies<br>* a right ventricular biopsy will be taken intraoperatively during either pulmonary endarterectomy (experimental group) or open cardiac surgery (control group).<br>|
| Other: Control group<br>Patients undergoing adult cardiac surgery without evidence of pulmonary hypertension. | Procedure: Right ventricular biopsies<br>* a right ventricular biopsy will be taken intraoperatively during either pulmonary endarterectomy (experimental group) or open cardiac surgery (control group).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| relationship between the metabolic, morphologic and functional alterations in the right ventricle |  | to investigate the relationship between the metabolic, morphologic and functional alterations in the right ventricle before surgery,one and six months after surgery. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| validation in human subjects of metabolic signaling pathway alterations found in animal model |  | analyse gene and protein expression during surgery |