Coronary Artery Disease in Patients With Friedreich's Ataxia
Condition: Friedreich Ataxia
MeSH terms: Ataxia; Cerebellar Ataxia; Friedreich Ataxia
Study type: Interventional

Summary: 
      Friedreich's ataxia is a debilitating, inherited disease cause by mutations in a protein
      called frataxin (FXN). FXN is one of several proteins that controls the production of
      iron-sulfur clusters, molecules that are essential for energy production in our cells as well
      as repair of our genetic code embedded in DNA molecules. Friedreich's ataxia (FRDA) and
      deficiency of FXN results in a nerve disease affecting coordination and a condition called
      hypertrophic cardiomyopathy (HCM), marked by an abnormal thickening of the heart. Patients
      with HCM can then develop pulmonary hypertension (PH), a deadly condition of the blood
      vessels of the lung. While most of the research in FRDA has focused on nerves and heart
      muscle, alterations in blood vessels of the heart and lung may worsen disease in FRDA. But,
      the role of FXN in these blood vessels has never been defined.

      Investigators pilot data suggest that Frataxin (FXN ) deficiency can control senescence and
      downstream function in various types of Endothelial cells (ECs), investigators hypothesize
      that Friedreich's Ataxia (FRDA) patients may demonstrate endothelial cells EC abnormalities
      throughout the vasculature potentially before overt cardiomyopathy develops.
    

Detailed description: 
      Procedure in details:

      Investigators have extensive experience in the performance of forearm blood flow studies
      using strain gauge plethysmography in patient volunteers. Endothelial dysfunction will be
      tested according to methodologies employed in our blood flow laboratories for more than a
      decade. Strain-gauge plethysmography is used to measure forearm blood flow during infusions
      of acetylcholine [ACh], and sodium nitroprusside [SNP] . Intra-arterial infusions of
      acetylcholine to test endothelium-dependent blood flow. Acetylcholine acts on muscarinic
      receptors to increase intracellular calcium levels and activate endothelial nitic oxide (NO)
      synthase. SNP is an exogenous source of NO, to assess endothelium-independent vasodilatation.

      Cumulative dose response curves will be constructed over 5-minute incremental infusions.
      Study doctor will proceed in the following order:

        -  SNP 0.8 1.6 and 3.2 mcg/min

        -  ACh 7.5 15 and 30 mcg/min

        -  Normal saline

      Forearm blood flow (FBF) measurements in both arms will be made using venous occlusion
      strain-gauge plethysmography prior to the initiation of any intra-arterial infusions. Blood
      pressure and heart rate will be measured during the procedure through the ECG. All FBF
      measurements will be expressed as mL/min per 100-1 mL forearm volume according to prior
      studies and the Whitney method.1, 2 Resting baseline FBF will be measured at least 30 minutes
      after venous and arterial catheter placement to ensure that blood flows in the cannulated
      arms are stabilized. Study team will measure FBF during the last 2 minutes of each infusion
      period. Infusions of individual vasoactive medications will occur over a 15-minute interval.
      There will be a 25-minute washout between vasoactive medications. The ACh 30 mcg/min will run
      for a total of 10 minutes.

      Test visit:

      The study will consist of one visit. Research nurse will do the lab work once subject arrive
      (results will take about an hour), and if eligible study team will proceed with the research
      procedure.

      All subjects scheduled for the visit will report to the CTRC on the morning of testing at
      8:00 AM. The subject will be placed in a quiet room with a where he will meet with the study
      doctor and CRC. The study doctor will discuss with the subject the nature of the research
      study, the risks of study participation, and participants' rights as a research subject. Then
      will ask subject to sign consent form. After signing the consent form, the study doctor will
      perform screening procedure which include the following:

        -  Asking questions concerning all medications prescriptions and non-prescription
           medications (vitamins, herbal supplements, aspirin, etc.) that are presently taking.
           Study team will be recording all this information in the subject's research record.

        -  Obtain a medical history and physical examination conducted by the study doctor.

        -  Will record height, weight, and vital signs of the subject.

        -  Research nurse will draw blood for laboratory testing. These tests will be a complete
           blood count (a test to make sure that subject is not anemic, or have too few red blood
           cells), electrolytes (tests to check the chemistry levels), glucose, and clotting tests.
           These tests will be performed to evaluate the health of subjects' body during study
           participation. Approximately 1 1/2 tablespoons (22 mL) of blood will be collected for
           this sample.

      All screening results will be reviewed by the study doctor prior to the procedure. Subject
      will be provided with any abnormal screening results so that he/she can follow up with their
      primary care doctor for further evaluation.

      All results of these screening reports will be read by our study doctors before initiating
      the study, it is possible that after taking these tests subject may not be able to take part
      in this study. The total duration of this visit is approximately 3-4 hours.

      Only 1 subject will be scheduled in the CTRC on any given testing day to meet appropriate
      clinical staffing requirements for the study.

      The CTRC nurse will place a peripheral 20-22-gauge venous catheter in the subject's
      antecubital vein of the non-dominant forearm for the purpose of collecting initial blood draw
      that will be used for research. After confirmation and documentation of dual arterial
      perfusion of the hand by an Allen's test, Dr. Risbano (co-investigator), is a critical care
      physician and qualified in this critical care procedure with 19 years' experience of doing
      arterial lines, will place an 20-22 brachial artery catheter in the non-dominant arm for
      infusion and blood pressure monitoring. Any non-PI physician will be personally supervised by
      the PI for three cannulations before allowing independent cannulation. Prior to the brachial
      artery catheter placement 1% lidocaine will be administered by injection for local
      anesthesia. Brachial artery catheterization is required for the strain gauge approach to
      locally administer the drugs to the forearm arterial circulation, while limiting systemic
      effect. The intra-arterial catheter will be connected by a 3-way stopcock to a pressure
      transducer for blood pressure measurements and to an infusion pump. Blood Flow Measurements:
      Heart rate, cardiac rhythm, respirations, blood pressure, and oxygen saturation will be
      continuously monitored. Forearm blood flow measurements will be performed by means of strain
      gauge venous-occlusion plethysmography, using methodology employed by the PI at the Vascular
      Medicine Branch of NHLBI in many other studies. plethysmography cuff pressure is
      intermittent. A mercury-filled Silastic strain gauge is placed around the widest portion of
      the forearm, and connected to a plethysmograph calibrated to measure the percent change in
      volume. The plethysmograph is connected to a strip chart recorder for forearm blood flow
      measurements following inflation of a wrist cuff to suprasystolic pressure to exclude the
      hand circulation. The cuff is inflated for a duration of 8-10 seconds over a 15 second
      interval. A blood pressure cuff on the upper arm is inflated to 40 mmHg for 7 seconds with a
      rapid cuff inflator in order to occlude venous outflow, but not arterial inflow, into the
      forearm. This causes non invisible distention of the forearm at a rate proportionate to
      arterial inflow. Blood pressure will be recorded directly from the intraarterial catheter
      immediately after each series of flow measurements. The use of dual arm plethysmography will
      allow a direct comparison of the non-instrumented arm (as a control) with the instrumented
      arm (research procedure), and serial measurements collected every 15 seconds during the
      research process.

      Upon completion of the research testing procedure, the study doctor will remove the venous
      and arterial catheters. A doctor will personally perform the decannulation procedure. The
      subject will be asked to remain in the supine position with the arm at or above heart level
      and to keep the arm still during the procedure. The doctor will ensure that all infusions are
      stopped and the stopcocks turned off to the patient. Any suture or tape used to secure the
      line will be removed using standard precautions. The cannula will then be removed and firm
      pressure held over the artery site with direct pressure of the thumb over sterile gauze for
      approximately 10 minutes at which time the doctor will check for any bleeding from the
      puncture site. If there is any bleeding, pressure will be held for an additional 10 minutes.
      Once there is no bleeding, a pressure dressing with Coban will be placed over the site. The
      subject will be instructed to remain in the supine position for an additional 10 minutes, and
      to remain in the study room for a 30-minute observation period. The arm will again be
      examined by the study physician prior to discharge of the subject at which time the doctor
      will instruct them regarding care of their arm and provide them with an instruction sheet.

      Medical Record Information: Study team will request subject's authorization to access medical
      record information from their past, current and future medical record information related to
      their health condition to be recorded into the Research study. This information will be
      collected from Heart and Vascular Institute (HVI) records, hospital records and, if
      applicable, private physician records. Since heart failure symptoms/progression may change
      over time, and these changes may be important to this study result, future medical records
      will be collected indefinitely. The medical record information contained within the study
      database will be used for research related purposes for an indefinite time. Subjects medical
      record information may be reviewed to see if they were eligible for any ongoing or future
      research studies; if they were eligible, then study team may contact subjects.

      Review of family history: For individuals who have a family history of FRDA, heart or lung
      disease, Study team may ask some basic information about other members of the family. Study
      team will not record in the Research study any identifiable information about individuals who
      have not signed consent to participate in this research.
    

Intervention name(s): plethysmography
Intervention type(s): Diagnostic Test
Intervention description(s): Forearm blood flow (FBF) measurements in both arms will be made using venous occlusion strain-gauge plethysmography prior to the initiation of any intra-arterial infusions. All FBF measurements will be expressed as mL/min per 100-1 mL forearm volume according to prior studies and the Whitney method.1, 2 Resting baseline FBF will be measured at least 30 minutes after venous and arterial catheter placement to ensure that blood flows in the cannulated arms are stabilized. We will measure FBF during the last 2 minutes of each infusion period. Infusions of individual vasoactive medications will occur over a 15-minute interval. There will be a 25-minute washout between vasoactive medications. Cumulative dose response curves will be constructed over 5-minute incremental infusions. We will proceed in the following order:
SNP 0.8, 1.6 and 3.2 mcg/min
ACh 7.5, 15 and 30 mcg/min
Normal saline
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic
Keywords: Friedreich's ataxia; frataxin; cardiomyopathy