Chronotropic Incompetence in Patients With HFpEF

• ClinicalTrials.gov Identifier: NCT02524145
• Recruitment Status: Completed
• First Posted: August 14, 2015
• Results First Posted: April 23, 2019
• Last Update Posted: April 23, 2019
• Sponsor: University of Texas Southwestern Medical Center
• Information provided by (Responsible Party): Benjamin Levine, University of Texas Southwestern Medical Center

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Basic Science
• Condition: Heart Failure
• Interventions: Other: Static Handgrip; Drug: Dexmedetomidine; Drug: Glycopyrrolate; Drug: Isoproterenol
• Enrollment: 40

Participant Flow

Recruitment Details	Recruitment initiated in June 2015 and completed October 2017. Subjects were recruited from academic medical center cardiology clinic. Healthy control subjects were recruited from the community.
Pre-assignment Details

Arm/Group Title	Healthy Seniors	HFpEF	Healthy Young
Arm/Group Description	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. Intervention: Static handgrip and Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.	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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.	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) Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.
Period Title: Overall Study
Started	15	15	10
Completed	13	13	7
Not Completed	2	2	3
Reason Not Completed
Withdrawal by Subject	2	2	3

Baseline Characteristics

Arm/Group Title		Healthy Seniors	HFpEF	Healthy Young	Total
Arm/Group Description		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. Intervention: Static handgrip and Autonomic Blockade (Dexmedetomidine, Glycopyrrolate, Isoproterenol) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.	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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.	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) Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.	Total of all reporting groups
Overall Number of Baseline Participants		15	15	10	40
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants	15 participants	10 participants	40 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	1 6.7%	6 40.0%	10 100.0%	17 42.5%
	>=65 years	14 93.3%	9 60.0%	0 0.0%	23 57.5%
Age, Continuous [1]; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	13 participants	13 participants	7 participants	33 participants
		71 (4)	68 (6)	31 (4)	61 (17)
		[1] Measure Analysis Population Description: Two senior controls, three young controls and two HFpEF subjects withdrew consent.
Sex: Female, Male [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	13 participants	13 participants	7 participants	33 participants
	Female	6 46.2%	7 53.8%	1 14.3%	14 42.4%
	Male	7 53.8%	6 46.2%	6 85.7%	19 57.6%
		[1] Measure Analysis Population Description: Two senior controls, three young controls and two HFpEF subjects withdrew consent.
Ethnicity (NIH/OMB) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	13 participants	13 participants	7 participants	33 participants
	Hispanic or Latino	0 0.0%	1 7.7%	1 14.3%	2 6.1%
	Not Hispanic or Latino	13 100.0%	12 92.3%	6 85.7%	31 93.9%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
		[1] Measure Analysis Population Description: Two senior controls, three young controls and two HFpEF subjects withdrew consent.
Race (NIH/OMB) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	13 participants	13 participants	7 participants	33 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	2 28.6%	2 6.1%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 7.7%	2 15.4%	1 14.3%	4 12.1%
	White	12 92.3%	11 84.6%	4 57.1%	27 81.8%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
		[1] Measure Analysis Population Description: Two senior controls, three young controls and two HFpEF subjects withdrew consent.
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	15 participants	15 participants	10 participants	40 participants
		15	15	10	40
Exercise heart rate [1]; Mean (Standard Deviation); Unit of measure: Beats per minute
	Number Analyzed	13 participants	13 participants	7 participants	33 participants
		156 (15)	117 (15)	190 (8)	148 (32)
		[1] Measure Analysis Population Description: Two senior control, three young control and two HFPEF subjects withdrew after consent.
Beta-receptor function [1]; Mean (Standard Deviation); Unit of measure: Beats per ng/kg/min
	Number Analyzed	13 participants	13 participants	7 participants	33 participants
		0.254 (0.166)	0.156 (0.133)	0.365 (0.129)	0.239 (0.163)
		[1] Measure Analysis Population Description: Two senior controls, three young controls and two HFpEF subjects withdrew consent

Outcome Measures

1. Primary Outcome

Title	Cardiac Beta-receptor Sensitivity
Description	Cardiac beta-receptor sensitivity will be measured by calculating slope of heart rate versus isoproterenol serum level.
Time Frame	1 day; primary outcome was complete for each subject in 1 day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Seniors	HFpEF	Healthy Young
Arm/Group Description:	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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.	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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.	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) Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.
Overall Number of Participants Analyzed	13	13	7
Mean (Standard Deviation); Unit of Measure: beats per ng/kg/min ISO
	0.254 (0.166)	0.156 (0.133)	0.365 (0.129)

2. Primary Outcome

Title	Central Command Regulation of Heart Rate
Description	Heart rate response to static hand grip immediately followed by supra-systolic arm occlusion and release will determine adequacy on central command control over heart rate response during exercise.
Time Frame	1 day; primary outcome was complete for each subject in 1 day

Outcome Measure Data

Analysis Population Description

Young subjects did not perform handgrip portion of the study.

Arm/Group Title	Healthy Seniors	HFpEF
Arm/Group Description:	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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.	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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.
Overall Number of Participants Analyzed	15	15
Mean (Standard Deviation); Unit of Measure: beats per minute
	93 (11)	89 (14)

Adverse Events

Time Frame	2 years
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Healthy Seniors	HFpEF	Healthy Young
Arm/Group Description	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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.	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) Static Handgrip: Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue. Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.	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) Autonomic Blockade: Subjects will be given dexmedetomidine and glycopyrrolate to suppress neural control over heart rate during isoproterenol infusion.
All-Cause Mortality
	Healthy Seniors	HFpEF	Healthy Young
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/13 (0.00%)	0/13 (0.00%)	0/7 (0.00%)
Serious Adverse Events
	Healthy Seniors	HFpEF	Healthy Young
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/13 (0.00%)	0/13 (0.00%)	0/7 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Healthy Seniors	HFpEF	Healthy Young
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/13 (0.00%)	0/13 (0.00%)	0/7 (0.00%)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr. Satyam Sarma
• Organization: University of Texas Southwestern Medical Center
• Phone: 214-345-7111
• EMail: SatyamSarma2@texashealth.org

• Responsible Party: Benjamin Levine, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT02524145 History of Changes
• Other Study ID Numbers: UTexasSouthwestern
• First Submitted: August 10, 2015
• First Posted: August 14, 2015
• Results First Submitted: December 18, 2018
• Results First Posted: April 23, 2019
• Last Update Posted: April 23, 2019