<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03816540</url>
  </required_header>
  <id_info>
    <org_study_id>1151848</org_study_id>
    <nct_id>NCT03816540</nct_id>
  </id_info>
  <brief_title>Diaphragmatic Breathing and Heart Rate Variability Training for Improving Hypertension in Fragile X Associated Tremor/Ataxia</brief_title>
  <official_title>Diaphragmatic Breathing and Heart Rate Variability Training for Improving Hypertension in Fragile X Associated Tremor/Ataxia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, Davis</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>UC Davis MIND Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>UC Davis, Mini-Grant Geriatrics</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, Davis</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To study whether heart rate variability training and respiratory coherence can improve&#xD;
      hypertension in individuals with FXTAS.&#xD;
&#xD;
      All patients will receive HRV biofeedback training for 20 sessions. Our hypothesis is that&#xD;
      individuals with FXTAS who undergo 20 sessions of biofeedback training will improve&#xD;
      self-regulatory skills for reducing hypertension, as measured by blood pressure measurement&#xD;
      to below 140/90. The investigators hypothesize that individuals who successfully develop&#xD;
      increased heart rate variability and better synchrony between heart rhythm and respiration&#xD;
      will show the greatest improvements in self-regulatory skills for hypertension.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Fragile X-associated tremor ataxia syndrome (FXTAS) is a late onset neurodegenerative disease&#xD;
      that affects carriers of the fragile X premutation. This project proposes the evaluation of&#xD;
      an innovative intervention program that promotes self-regulatory skills for hypertension in&#xD;
      individuals with FXTAS. Using a control-group experimental design, the investigators propose&#xD;
      to explore the efficacy of a biofeedback treatment to support self-regulatory processes on&#xD;
      the physiological level: Heart Rate Variability (HRV) and respiratory coherence biofeedback.&#xD;
&#xD;
      Chronic hypertension contributes to cardiovascular complications, dementia, and increased&#xD;
      risk of stroke. Our results indicate that the risk of hypertension is significantly elevated&#xD;
      in male premutation carriers with FXTAS compared with carriers without FXTAS and controls.&#xD;
&#xD;
      Several research studies showed high levels of physiological arousal in individuals with&#xD;
      Fragile X-Associated Disorders (FXS/FX-AD), related to a dysregulation of the sympathetic and&#xD;
      parasympathetic nervous system. One parameter to measure physiological arousal is&#xD;
      cardiovascular activity. It provides an index of parasympathetic and sympathetic involvement&#xD;
      of the autonomic nervous system. Heart rate is under the control of efferent sympathetic and&#xD;
      vagal activities directed to the sinus node, which are modulated by central brain stem&#xD;
      (vasomotor and respiratory centers) and peripheral oscillators (oscillation in arterial&#xD;
      pressure and respiratory movements). Spectral analysis of heart rate variability (HRV) is a&#xD;
      reliable quantitative method for analyzing the modulatory effects of neural mechanisms on the&#xD;
      sinus node.&#xD;
&#xD;
      Biofeedback treatments are reported for over 30 years. Biofeedback provides specific&#xD;
      information about internal biological processes (i.e. muscle activity, respiration, heart&#xD;
      rate variability, skin temperature and brain electrical activity) in an individual. In&#xD;
      general, by enhancing the awareness of these processes and training to volitional control&#xD;
      over them, specific parameters can be improved. The internal biological processes can be&#xD;
      measured with a specific biofeedback equipment that convert this data into signals, often in&#xD;
      the form of auditory, visual or somatosensory events, so that the individual can perceive&#xD;
      real-time changes in their physiological activity. As the individual learns to control these&#xD;
      events, healthier physiological processes are conditioned. Depending upon the physiological&#xD;
      processes targeted, healthier patterns of activity can be achieved by most people after they&#xD;
      have participated in 10 to 50 sessions of biofeedback supported with professional coaching&#xD;
      and practice. Various biofeedback protocols and assistive electronic technologies such as the&#xD;
      NeXus-10, emWave Personal Stress Reliever® or StressEraser® exist to enhance the balance of&#xD;
      parasympathetic activity, vagal tone, increase HRV and synchronize respiration with the heart&#xD;
      rhythm (i.e., the slowing down and speeding up of the heart over time).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 1, 2018</start_date>
  <completion_date type="Actual">March 13, 2019</completion_date>
  <primary_completion_date type="Actual">March 13, 2019</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Same intervention will be applied to FXTAS-affected and unaffected (comparison) participants.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in blood pressure (systolic &amp; diastolic)</measure>
    <time_frame>Baseline, 4 to 6 weeks</time_frame>
    <description>Blood pressure is measured at the brachial artery of left arm using an electronic blood pressure monitor with an inflatable cuff, repeated three times at each site, and averaged. Less than 120/80 mmHg is considered &quot;normal,&quot; 120/80 to 139/89 mmHg is &quot;prehypertension,&quot; and above 140/90 mmHg is &quot;hypertension.&quot;</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical Global Impression Scale - Severity (CGI-S)</measure>
    <time_frame>Baseline</time_frame>
    <description>The CGI-Severity (CGI-S) will be assessed at baseline according to the severity of hypertension, which is rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline elevated; 3=mildly elevated; 4=moderately elevated; 5=markedly elevated; 6=severely elevated; 7= extremely elevated. This rating is based upon observed and reported symptoms, behavior, and function in the past seven days. Symptoms and behavior can fluctuate over a week; the score should reflect the average severity level across the seven days.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical Global Impression Scale - Improvement (CGI-I)</measure>
    <time_frame>4 to 6 weeks</time_frame>
    <description>The CGI-Improvement (CGI-I) is similar to the CGI-S. Directly post-treatment and at the follow-up, the investigator compares the patient's overall clinical condition to the one week period just prior to the baseline visit. The query hypertension is rated on a seven-point scale: &quot;Compared to the patient's condition at baseline, this participant's condition is: 1=very much improved since the baseline; 2=much improved; 3=minimally improved; 4=no change from baseline; 5=minimally worse; 6= much worse; 7=very much worse since the baseline measure.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Psychophysiological Profile - Heart Rate Variability (HRV)</measure>
    <time_frame>4 to 6 weeks</time_frame>
    <description>HRV will be assessed using the emwave2 desktop device (HeartMath Institute, Boulder Creek, CA). It uses an earlobe plethysmograph sensor to detect the pulse wave, and plots changes in heart rate on a beat-to-beat basis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Psychophysiological Profile - Synchrony between Respiration and HRV</measure>
    <time_frame>4 to 6 weeks</time_frame>
    <description>A measure of synchrony will be assessed which will be calculated using the HRV measure previously described and respiration, which will be recorded by strain gauges placed around the abdomen.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Psychophysiological Profile - Skin Conductance</measure>
    <time_frame>4 to 6 weeks</time_frame>
    <description>Galvanic skin response is measured in Siemens by the skin's conductance between two small metal electrodes placed on the walls of the index finger tip and the ring finger tip.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mini-Mental State Examination (MMSE)</measure>
    <time_frame>4 to 6 weeks</time_frame>
    <description>The Mini-Mental State Examination (MMSE) or Folstein test is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It is commonly used in medicine and allied health to screen for dementia.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Hypertension</condition>
  <condition>FXTAS</condition>
  <arm_group>
    <arm_group_label>FXTAS-affected</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>FXTAS-affected participants will receive HRV and respiratory coherence biofeedback training for 20 sessions.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>FXTAS-unaffected</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>FXTAS-unaffected participants will be assessed to compare the effects of biofeedback based on FXTAS status. This arm will receive HRV and respiratory coherence biofeedback training for 20 sessions.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>HRV and respiratory coherence biofeedback</intervention_name>
    <description>Biofeedback treatment to support self-regulatory processes on the physiological level: heart rate variability (HRV) and respiratory coherence.</description>
    <arm_group_label>FXTAS-affected</arm_group_label>
    <arm_group_label>FXTAS-unaffected</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Males and females between the ages of 50-90 with a molecular documentation of a&#xD;
             fragile X premutation, diagnosed with FXTAS.&#xD;
&#xD;
          2. stable current pharmacological treatment regimen for at least 4 weeks.&#xD;
&#xD;
          3. English speaking (the intervention is currently only available in English)&#xD;
&#xD;
          4. Clinically significant hypertension.&#xD;
&#xD;
          5. Normal or corrected to normal vision and hearing.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Significant medical and behavioral problems that would interfere with the study (e.g.&#xD;
             not being able to sit and play a computer game for 10 minutes)&#xD;
&#xD;
          2. Participants who plan to initiate or change pharmacologic or non-pharmacologic&#xD;
             interventions during the course of the study&#xD;
&#xD;
          3. Individual is non-verbal (has no spoken language)&#xD;
&#xD;
          4. English is not the primary language.&#xD;
&#xD;
          5. Clinically critical Hypertension that requires medical attention&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University of California, Davis, MIND Institute</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Bradley RT, McCraty R, Atkinson M, Tomasino D, Daugherty A, Arguelles L. Emotion self-regulation, psychophysiological coherence, and test anxiety: results from an experiment using electrophysiological measures. Appl Psychophysiol Biofeedback. 2010 Dec;35(4):261-83. doi: 10.1007/s10484-010-9134-x.</citation>
    <PMID>20559707</PMID>
  </reference>
  <reference>
    <citation>Lehrer PM, Vaschillo E, Vaschillo B. Resonant frequency biofeedback training to increase cardiac variability: rationale and manual for training. Appl Psychophysiol Biofeedback. 2000 Sep;25(3):177-91. doi: 10.1023/a:1009554825745.</citation>
    <PMID>10999236</PMID>
  </reference>
  <reference>
    <citation>Lloyd A, Brett D, Wesnes K. Coherence training in children with attention-deficit hyperactivity disorder: cognitive functions and behavioral changes. Altern Ther Health Med. 2010 Jul-Aug;16(4):34-42.</citation>
    <PMID>20653294</PMID>
  </reference>
  <reference>
    <citation>Hamlin AA, Sukharev D, Campos L, Mu Y, Tassone F, Hessl D, Nguyen DV, Loesch D, Hagerman RJ. Hypertension in FMR1 premutation males with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Am J Med Genet A. 2012 Jun;158A(6):1304-9. doi: 10.1002/ajmg.a.35323. Epub 2012 Apr 23.</citation>
    <PMID>22528549</PMID>
  </reference>
  <reference>
    <citation>Pagani M, Rimoldi O, Pizzinelli P, Furlan R, Crivellaro W, Liberati D, Cerutti S, Malliani A. Assessment of the neural control of the circulation during psychological stress. J Auton Nerv Syst. 1991 Jul;35(1):33-41. doi: 10.1016/0165-1838(91)90036-3.</citation>
    <PMID>1940025</PMID>
  </reference>
  <reference>
    <citation>Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996 Mar 1;93(5):1043-65. No abstract available.</citation>
    <PMID>8598068</PMID>
  </reference>
  <reference>
    <citation>Lubar JF, Bahler WW. Behavioral management of epileptic seizures following EEG biofeedback training of the sensorimotor rhythm. Biofeedback Self Regul. 1976 Mar;1(1):77-104. doi: 10.1007/BF00998692.</citation>
    <PMID>825150</PMID>
  </reference>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>May 8, 2018</study_first_submitted>
  <study_first_submitted_qc>January 23, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 25, 2019</study_first_posted>
  <last_update_submitted>October 18, 2019</last_update_submitted>
  <last_update_submitted_qc>October 18, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 22, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03816540
org study id: 1151848
nct id: NCT03816540
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
To study whether heart rate variability training and respiratory coherence can improve
      hypertension in individuals with FXTAS.

      All patients will receive HRV biofeedback training for 20 sessions. Our hypothesis is that
      individuals with FXTAS who undergo 20 sessions of biofeedback training will improve
      self-regulatory skills for reducing hypertension, as measured by blood pressure measurement
      to below 140/90. The investigators hypothesize that individuals who successfully develop
      increased heart rate variability and better synchrony between heart rhythm and respiration
      will show the greatest improvements in self-regulatory skills for hypertension.
Fragile X-associated tremor ataxia syndrome (FXTAS) is a late onset neurodegenerative disease
      that affects carriers of the fragile X premutation. This project proposes the evaluation of
      an innovative intervention program that promotes self-regulatory skills for hypertension in
      individuals with FXTAS. Using a control-group experimental design, the investigators propose
      to explore the efficacy of a biofeedback treatment to support self-regulatory processes on
      the physiological level: Heart Rate Variability (HRV) and respiratory coherence biofeedback.

      Chronic hypertension contributes to cardiovascular complications, dementia, and increased
      risk of stroke. Our results indicate that the risk of hypertension is significantly elevated
      in male premutation carriers with FXTAS compared with carriers without FXTAS and controls.

      Several research studies showed high levels of physiological arousal in individuals with
      Fragile X-Associated Disorders (FXS/FX-AD), related to a dysregulation of the sympathetic and
      parasympathetic nervous system. One parameter to measure physiological arousal is
      cardiovascular activity. It provides an index of parasympathetic and sympathetic involvement
      of the autonomic nervous system. Heart rate is under the control of efferent sympathetic and
      vagal activities directed to the sinus node, which are modulated by central brain stem
      (vasomotor and respiratory centers) and peripheral oscillators (oscillation in arterial
      pressure and respiratory movements). Spectral analysis of heart rate variability (HRV) is a
      reliable quantitative method for analyzing the modulatory effects of neural mechanisms on the
      sinus node.

      Biofeedback treatments are reported for over 30 years. Biofeedback provides specific
      information about internal biological processes (i.e. muscle activity, respiration, heart
      rate variability, skin temperature and brain electrical activity) in an individual. In
      general, by enhancing the awareness of these processes and training to volitional control
      over them, specific parameters can be improved. The internal biological processes can be
      measured with a specific biofeedback equipment that convert this data into signals, often in
      the form of auditory, visual or somatosensory events, so that the individual can perceive
      real-time changes in their physiological activity. As the individual learns to control these
      events, healthier physiological processes are conditioned. Depending upon the physiological
      processes targeted, healthier patterns of activity can be achieved by most people after they
      have participated in 10 to 50 sessions of biofeedback supported with professional coaching
      and practice. Various biofeedback protocols and assistive electronic technologies such as the
      NeXus-10, emWave Personal Stress Reliever® or StressEraser® exist to enhance the balance of
      parasympathetic activity, vagal tone, increase HRV and synchronize respiration with the heart
      rhythm (i.e., the slowing down and speeding up of the heart over time).
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: Same intervention will be applied to FXTAS-affected and unaffected (comparison) participants.
primary purpose: Treatment
masking: None (Open Label)
measure: Change in blood pressure (systolic & diastolic)
time frame: Baseline, 4 to 6 weeks
description: Blood pressure is measured at the brachial artery of left arm using an electronic blood pressure monitor with an inflatable cuff, repeated three times at each site, and averaged. Less than 120/80 mmHg is considered "normal," 120/80 to 139/89 mmHg is "prehypertension," and above 140/90 mmHg is "hypertension."
measure: Clinical Global Impression Scale - Severity (CGI-S)
time frame: Baseline
description: The CGI-Severity (CGI-S) will be assessed at baseline according to the severity of hypertension, which is rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline elevated; 3=mildly elevated; 4=moderately elevated; 5=markedly elevated; 6=severely elevated; 7= extremely elevated. This rating is based upon observed and reported symptoms, behavior, and function in the past seven days. Symptoms and behavior can fluctuate over a week; the score should reflect the average severity level across the seven days.
measure: Clinical Global Impression Scale - Improvement (CGI-I)
time frame: 4 to 6 weeks
description: The CGI-Improvement (CGI-I) is similar to the CGI-S. Directly post-treatment and at the follow-up, the investigator compares the patient's overall clinical condition to the one week period just prior to the baseline visit. The query hypertension is rated on a seven-point scale: "Compared to the patient's condition at baseline, this participant's condition is: 1=very much improved since the baseline; 2=much improved; 3=minimally improved; 4=no change from baseline; 5=minimally worse; 6= much worse; 7=very much worse since the baseline measure.
measure: Psychophysiological Profile - Heart Rate Variability (HRV)
time frame: 4 to 6 weeks
description: HRV will be assessed using the emwave2 desktop device (HeartMath Institute, Boulder Creek, CA). It uses an earlobe plethysmograph sensor to detect the pulse wave, and plots changes in heart rate on a beat-to-beat basis.
measure: Psychophysiological Profile - Synchrony between Respiration and HRV
time frame: 4 to 6 weeks
description: A measure of synchrony will be assessed which will be calculated using the HRV measure previously described and respiration, which will be recorded by strain gauges placed around the abdomen.
measure: Psychophysiological Profile - Skin Conductance
time frame: 4 to 6 weeks
description: Galvanic skin response is measured in Siemens by the skin's conductance between two small metal electrodes placed on the walls of the index finger tip and the ring finger tip.
measure: Mini-Mental State Examination (MMSE)
time frame: 4 to 6 weeks
description: The Mini-Mental State Examination (MMSE) or Folstein test is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. It is commonly used in medicine and allied health to screen for dementia.
arm group label: FXTAS-affected
arm group type: Experimental
description: FXTAS-affected participants will receive HRV and respiratory coherence biofeedback training for 20 sessions.
arm group label: FXTAS-unaffected
arm group type: Active Comparator
description: FXTAS-unaffected participants will be assessed to compare the effects of biofeedback based on FXTAS status. This arm will receive HRV and respiratory coherence biofeedback training for 20 sessions.
intervention type: Device
intervention name: HRV and respiratory coherence biofeedback
description: Biofeedback treatment to support self-regulatory processes on the physiological level: heart rate variability (HRV) and respiratory coherence.
arm group label: FXTAS-affected
arm group label: FXTAS-unaffected
criteria: 
gender: All
minimum age: 50 Years
maximum age: 90 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United States
citation: Bradley RT, McCraty R, Atkinson M, Tomasino D, Daugherty A, Arguelles L. Emotion self-regulation, psychophysiological coherence, and test anxiety: results from an experiment using electrophysiological measures. Appl Psychophysiol Biofeedback. 2010 Dec;35(4):261-83. doi: 10.1007/s10484-010-9134-x.
PMID: 20559707
citation: Lehrer PM, Vaschillo E, Vaschillo B. Resonant frequency biofeedback training to increase cardiac variability: rationale and manual for training. Appl Psychophysiol Biofeedback. 2000 Sep;25(3):177-91. doi: 10.1023/a:1009554825745.
PMID: 10999236
citation: Lloyd A, Brett D, Wesnes K. Coherence training in children with attention-deficit hyperactivity disorder: cognitive functions and behavioral changes. Altern Ther Health Med. 2010 Jul-Aug;16(4):34-42.
PMID: 20653294
citation: Hamlin AA, Sukharev D, Campos L, Mu Y, Tassone F, Hessl D, Nguyen DV, Loesch D, Hagerman RJ. Hypertension in FMR1 premutation males with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Am J Med Genet A. 2012 Jun;158A(6):1304-9. doi: 10.1002/ajmg.a.35323. Epub 2012 Apr 23.
PMID: 22528549
citation: Pagani M, Rimoldi O, Pizzinelli P, Furlan R, Crivellaro W, Liberati D, Cerutti S, Malliani A. Assessment of the neural control of the circulation during psychological stress. J Auton Nerv Syst. 1991 Jul;35(1):33-41. doi: 10.1016/0165-1838(91)90036-3.
PMID: 1940025
citation: Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation. 1996 Mar 1;93(5):1043-65. No abstract available.
PMID: 8598068
citation: Lubar JF, Bahler WW. Behavioral management of epileptic seizures following EEG biofeedback training of the sensorimotor rhythm. Biofeedback Self Regul. 1976 Mar;1(1):77-104. doi: 10.1007/BF00998692.
PMID: 825150
responsible party type: Sponsor
mesh term: Hypertension
sharing ipd: No