Conditions: Heart Failure
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: yes

Brief summary:
The purpose of this study is to determine the mechanisms of chronotropic incompetence (inability to increase heart rate with exercise) in patients with heart failure and preserved ejection fraction (HFpEF). The investigators will test both central command regulation and cardiac beta-receptor sensitivity over control of heart rate.

Detailed description:
About half of all elderly patients with a diagnosis of congestive heart failure have apparently normal systolic function, so called "heart failure with a preserved ejection fraction" or HFpEF. To date, no effective therapy for HFpEF has been found, in part because of failure to discern key pathophysiologic pathways.

Although HFpEF is a complex disease with multiple pathophysiologic pathways leading to the phenotype of heart failure, virtually all proposed mechanisms involve some impairment of diastolic function - the inability of the heart to fill adequately at a low enough pressure to avoid congestion which during physical activity or exercise, prevent an increase in heart rate. A number of studies have purported the inability to increase heart rate (chronotropic incompetence) is responsible for the diminished exercise capacity.

Alternatively, the investigators hypothesize that the stiff, slowly relaxing heart of patients with HFpEF causes a marked elevation in pulmonary capillary pressure during exercise which leads to premature fatigue prior to achieving maximal heart rate, thus causing apparent "chronotropic incompetence".

Arms:
arm 1: Fifteen healthy senior volunteers \> 60 years of age. Subjects will be healthy with no chronic medical problems and on no cardiac medications except for statins. All control subjects will have a Body Mass Index (BMI) \<30, with exercise histories of less than 3 days per week of aerobic exercise.

Intervention: Static handgrip and Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) arm 2: Patients with HFpEF will provide data from their cardiologist or primary care physician that confirm the following: a) signs and symptoms of heart failure; b) an ejection fraction \> 0.50; and c) objective evidence of diastolic dysfunction.

Intervention: Static handgrip and Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) arm 3: Fifteen volunteers \<45 yrs will be enrolled. Subjects will be healthy with no chronic medical problems and on no cardiac medications except for statins and have BMI \<30.

Intervention: Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol)

Interventions: intervention 1: Static Handgrip intervention 2: Dexmedetomidine intervention 3: Glycopyrrolate intervention 4: Isoproterenol
Intervention descriptions: intervention 1: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. intervention 2: Subjects will be given dexmedetomidine to suppress sympathetic outflow to minimize sympathetic control over resting heart rate. Subjects will then be given glycopyrrolate to suppress parasympathetic tone to minimize parasympathetic control over resting heart rate. After achievement of autonomic blockade, cardiac beta receptor sensitivity will be assessed by graded infusions of isoproterenol until heart rate increases 30 beats above baseline. intervention 3: Subjects will be given dexmedetomidine to suppress sympathetic outflow to minimize sympathetic control over resting heart rate. Subjects will then be given glycopyrrolate to suppress parasympathetic tone to minimize parasympathetic control over resting heart rate. After achievement of autonomic blockade, cardiac beta receptor sensitivity will be assessed by graded infusions of isoproterenol until heart rate increases 30 beats above baseline. intervention 4: Subjects will be given dexmedetomidine to suppress sympathetic outflow to minimize sympathetic control over resting heart rate. Subjects will then be given glycopyrrolate to suppress parasympathetic tone to minimize parasympathetic control over resting heart rate. After achievement of autonomic blockade, cardiac beta receptor sensitivity will be assessed by graded infusions of isoproterenol until heart rate increases 30 beats above baseline.

Protocol document:
Prot_000.pdf: 
Study Title: Determinants of Chronotropic Incompetence in Patients with Heart 
Failure and a Preserved Ejection Fraction (HFpEF)  
NCT 02524145 
December 1, 2014 
 
Sponsor/Funding Source: NIH/NIA  
 
PURPOSE:  
The purpose of this study is to test the hypothesis that chronotropic competence (the ability to 
increase heart rate during exercise), as assessed by the HR response to beta-adrenergic 
stimulation and increasing central command, is preserved in patients with heart failure and a 
preserved ejection fraction (HFpEF) compared to healthy age-matched controls.  
Study Design:  
To assess our hypothesis, we will need to complete screening on 15 patients with HFpEF and 
30 healthy control subjects. Screening will occur after informed consent and include history and 
physical, screening EKG, bloodwork for potassium levels and renal function. Following 
screening, all 45 participants will complete Day 1 testing, including familiarization and a maximal 
exercise test with cardiopulmonary stress echocardiogram. This testing determines maximal 
exercise capacity, the HR/work rate relationship, and excludes provocable ischemia. However, 
not every subject who enrolls in the study will go onto complete all testing. During this Day 1 
testing, exclusion criteria may be identified requiring disqualification from the study; examples 
include manifest ischemic heart disease, valvular disease, or the identification of coronary artery 
disease in the healthy subjects.  
The 2nd day of testing for all qualified subjects will include static handgrip exercises to 
determine heart rate response to central command and drug infusion studies using 
glycopyrrolate, dexmedetomidine and isoproterenol to assess adrenergic response.  
STUDY PROCEDURES  
1) Day 1: This visit consists primarily of a maximal exercise test with the measurement of echo 
derived wall motion and systolic volumes, blood pressure, ECG, heart rate, oxygen uptake, 
cardiac output (acetylene re-breathing method), stroke volume, total peripheral resistance, and 
a-vO2 difference. Goals of this day are to: 1) estimate the peak VO2; 2) carefully assess for the 
presence of provocable ischemia via both ECG and contractile imaging.  
 
2) Day 2: This visit consists of the hand grip test, drug infusion study and will last approximately 
4.5 hours. This visit will assess central command and measure beta-adrenergic 
responsiveness/sensitivity. a. Instrumentation –. Subjects will first empty their bladders to avoid 
any urinary retention problems from glycopyrrolate/dexmedetomidine administration. They will 
then be instrumented with an ECG for HR, pulse oximeter for oxygen saturation, a finger and 
arm cuff for BP and 2 peripheral IVs.  
b. After 20 minutes in the supine position, baseline data will be collected including the HR and 
blood pressure response to fatiguing static handgrip exercise at 40% of a maximum voluntary 
contraction followed by 2 minutes of post-exercise circulatory arrest (see enclosed manuscript 
for experimental details). This protocol will allow the quantification of the HR response to central 
command.  
c. Complete autonomic blockade will then be established with a 15 ug/kg bolus of glycopyrrolate 
followed by 7 ug/kg/hr maintenance infusion. Heart rate may increase slightly after the bolus 
and subjects will be observed for 15 minutes (establishes steady state) before proceeding to 
dexmedetomidine infusion. Dexmedetomidine will then be  
 
 
 


given as an IV bolus of 0.225 ug/kg over 6 minutes followed by maintenance rate of 0.3 – 0.5 
ug/kg/hr. The maintenance dose will start at 0.3 ug/kg/hr and increased to 0.5 ug/kg/hr if 
necessary (see next subheading). Subjects will be monitored closely with a pulse oximeter and 
respirometer to monitor the sedating effects of dexmedetomidine. One of the medications 
(glycopyrrolate) may also cause dry mouth and urinary retention which resolves as the 
medication wears off within 1 to 2 hours. To minimize or alleviate dry mouth, we offer subjects 
Biotene Moisturizing Mouth Spray. We offer this spray several times throughout the drug study 
to minimize the sensation of dry mouth and improve comfort level when the subjects are on the 
mouthpiece. This is an over-the-counter medication comprised of water, glycerin and castor oil. 
It is sugar and alcohol free. Subjects will also be queried every 5 minutes during infusion 
regarding sedation status using a visual analog scale (0 – 100; 0 – completely alert, 100 – very 
sedated). The combination of glycopyrrolate/dexmedetomidine (gly/dex) achieves central 
autonomic blockade similar to pentolinium and trimethaphan, two drugs previously used but that 
have since been discontinued for clinical use. Dr. Levine’s collaborator and colleague Dr. 
Michael Joyner (Mayo Clinic, Rochester, MN) has used this gly/dex combination in previous 
studies (see attached publication). In addition, our group has extensive experience with 
ganglionic blocking agents and Dr. Levine has an IND for trimethaphan (seen enclosed 
publications). However trimethaphan and pentolinum are no longer available even for 
experimental studies thus forcing us to seek other alternatives.  
d. 20 minutes following administration of gly/dex, a Valsalva maneuver will be performed (30 
mmHg x 20 seconds) to document the absence of autonomic reflexes as previously described. 
If there is still a > 10 bpm rise in HR, dexmedetomidine maintenance infusion will be increased 
to 0.4 ug/kg/hr and Valsalva will be rechecked in 20 minutes. If HR responsiveness is still 
present, the maintenance dose will be increased again to 0.5 ug/kg/hr.  
e. Resting cardiovascular variables including HR, BP, and non-invasive cardiac output will then 
be repeated. This will establish the intrinsic heart rate (i.e., the HR in the absence of autonomic 
influences).  
f. Isoproterenol will then be infused at 3.5, 7.0, 14.0, and 35 ng/kg/min with each stage lasting 6 
minutes each. During each infusion, HR will be measured from minute 4:30 to 5:00 of each 
infusion. The infusion will be stopped when the HR rises by 30 bpm. At each infusion level, 10 
ml of blood will be drawn for isoproterenol and norepinephrine levels to be sent to the Goldstein 
lab at NIH at the same time as HR measured. This will allow us to calculate a true dose-
response relationship which will provide a robust measure of adrenergic sensitivity.  
g. Subjects will remain supine for ~ 2 hours, or until the Valsalva response returns to normal. 
They will not be allowed to leave until they are clearly making saliva, and have a normal BP 
during 5 minutes of quiet standing.  
 
 
BIOSTATISTICS:  
The project has been NIH reviewed and will not require a stats section.  
 
 
 
 
 
 
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