Genetic and Environmental Determinants That Control Metabolism in Pulmonary Hypertension

Study Overview
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Brief Summary
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The investigators are performing this research study to determine whether having low iron-sulfur cluster levels can cause a disease known as pulmonary hypertension (PH). PH is defined as abnormally high blood pressure in the arteries of the lungs. Usually, small specialized structures inside each human cell called mitochondria are in charge of generating energy within lung arteries for normal function. During situations of disease or stress, lung arteries undergo a change in the function of mitochondria, resulting in the development of PH. In studies on mice, investigators have learned that alterations in the production of specific metal complexes called iron-sulfur clusters are responsible for these changes. This makes it more likely that mice will develop PH. In this study, the investigators want to find out if alteration of iron-sulfur cluster formation leads to increased likelihood of developing PH in humans.

Detailed Description
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Test group: The study will include two visits for the test group: At visit one there will be required and optional research activities as the following: Required research activities: -Peripheral blood draw (3.5 tablespoons) drawn by research coordinator. This blood is to isolate PBMCs for generation of iPSCs.If patient did not want to give a blood sample we will ask if willing to give a urine sample. A clinical research coordinator will give the patient a plastic container and will explain how use it. The following research activities will be optional at visit one: Physical exam and blood work (kidney/liver, blood count, coagulation, B-HCG, iron studies, and plasma for microRNA) processed at Presby Lab. This will be required if the patient approved to do right heart cath. Electrocardiogram. 6 Minute Walk Test. Skin Biopsy from underarm or inner thigh by physician (Dermatology department) (if patients agree to do, if not, we will only get a blood sample) Resting Echocardiogram This visit will last 7-8 hours. Study Visit Two: This will include optional Right Heart Catheterization. Right Heart catheterization by PI/Sub-Investigator. Duration   3 hours IF the results show that the pressure in the lung vessels is elevated without exercise AND there is no other abnormality in the heart function, we will NOT do exercise testing. IF the patients are physically able to perform exercise testing/agree to do an exercise testing, patients will have an Exercise Right Heart catheterization and a Rest and Stress Echocardiography. (Determined by PI/Sub-Investigator All participants who will do right heart catheterization will have to do a pregnancy test before the procedure. Exercise Echocardiogram completed in. If patient unable to exercise medication (Dobutamine) will be given. Duration   1-2 hours Exercise Right Heart catheterization Duration   2-3 hours CONTROL GROUP Control group will only have one visit. At this visit there will be a minimum required research activity to participate in the study and this will include: -Peripheral blood draw (3.5 tablespoons) drawn by research coordinator. This blood is to isolate PBMCs for generation of iPSCs. If participant did not want to give a blood sample we will ask if willing to give a urine sample. The following research activists will be optional at visit one: Physical exam and blood work (kidney/liver, blood count, coagulation, B-HCG, iron studies, and plasma for microRNA) processed at Presby Lab. This will be required if the patient approved to do right heart cath. ECG, done by research coordinator and read by PI/Sub-Investigator. 6 Minute Walk Test, done by research coordinator, if patient could perform. Skin Biopsy from underarm or inner thigh by physician (Dermatology department) (if patients agree to do, if not, we will only get a blood sample) This visit will last 6-7 hours.

Official Title
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Genetic and Environmental Determinants That Control Metabolism in Pulmonary Hypertension

Conditions
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Iron-sulfur Cluster Deficiency, Pulmonary Hypertension, Friedreich Ataxia

Intervention / Treatment
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* Procedure: Right Heart Catheterization
* Other: Blood draw


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA for Test Group: Consenting individuals age 18-60 years of age Have a confirmed genetic homozygous mutation (including ISCU1/2, FXN, BOLA3, NFU1) that causes the impairment of iron-sulfur cluster formation; such a subject will not be excluded from this study even if that patient's first degree relative(s) does not enroll in this pilot study. INCLUSION CRITERIA for Control Group: Consenting individuals age 18-60 years of age First degree family member (mother, father, sister, brother, son, or daughter) of recruited individual in the test group Have a confirmed heterozygous genetic mutation (including ISCU1/2, FXN, BOLA3, NFU1) EXCLUSION CRITERIA for Test and Control Group: Impaired decision making capacity Inability to consent to procedures Children less than 18 years of age and adults older than 60 years of age Current pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Test Group<br>The study population will include ten patients (ages 18-60 yrs) with confirmed mutations of the iron-sulfur cluster biogenesis complex of proteins and experiencing dyspnea, heart failure, or exercise intolerance. | Procedure: Right Heart Catheterization<br>* Some participants (i.e., those that are willing and able) will undergo a Right Heart Catheterization to check Cardiopulmonary function.<br>Other: Blood draw<br>* Test and control group will be asked to give 20 ml of blood samples<br>|
| Control Group<br>It will also include ten additional patients (ages 18-60 yrs) who are unaffected first-degree family members of the above subjects. | Other: Blood draw<br>* Test and control group will be asked to give 20 ml of blood samples<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 minute walk distance (meters) | In the TEST group, the investigators will measure 6 minute walk distance | baseline | 
| Pulmonary arterial pressure (mm Hg) | In the TEST group, the investigators will measure pulmonary arterial pressure by right heart catheterization at rest and with exercise. | baseline |