Chronotropic Incompetence in Patients With HFpEF

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".

• Static Handgrip (Other): Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue.
• Dexmedetomidine (Drug), also known as Sympathetic blockade: 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.
• Glycopyrrolate (Drug), also known as Parasympathetic blockade: 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.
• Isoproterenol (Drug), also known as Beta-receptor sensitivity testing: 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.

Primary outcomes

• Cardiac Beta-receptor Sensitivity [1 day; primary outcome was complete for each subject in 1 day]: Cardiac beta-receptor sensitivity will be measured by calculating slope of heart rate versus isoproterenol serum level.
• Central Command Regulation of Heart Rate [1 day; primary outcome was complete for each subject in 1 day]: 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.

Sex: All, ages: 18 Years to 85 Years, accepts healthy volunteers

Healthy Controls

Inclusion Criteria:

* ages > 60 years
* body mass index <30
* absence of co-morbid conditions including hypertension, diabetes, heart failure, asthma, chronic obstructive pulmonary disease, coronary artery disease as evidenced by angina or prior myocardial infarction or cerebrovascular disease as evidenced by prior transient ischemic attack or stroke

Exclusion Criteria:

* ages less than 60
* body mass index >30
* presence of co-morbid conditions including hypertension, diabetes, heart failure, asthma, chronic obstructive pulmonary disease, coronary artery disease as evidenced by angina or prior myocardial infarction or cerebrovascular disease as evidenced by prior transient ischemic attack or stroke
* Patients with chronic orthopedic injury that might make them unable to participate in an exercise testing will also be excluded
* Subjects unable to speak English will not be recruited because of the complex experimental studies and the need for precise communication between the volunteers and the research staff to ensure safety.

HFpEF Subjects

Inclusion Criteria:

* Patients will be > 60 years old, male or female, all races.
* signs and symptoms of heart failure
* ejection fraction > 0.50
* objective evidence of diastolic dysfunction.
* All patients must be in sinus rhythm without a left bundle branch block at the time of study

Exclusion Criteria:

* underlying valvular or congenital heart disease
* restrictive or infiltrative cardiomyopathy
* acute myocarditis
* New York Heart Association (NYHA) Class IV congestive heart failure, or heart failure that cannot be stabilized on medical therapy
* other condition that would limit the patient's ability to complete the protocol
* manifest ischemic heart disease
* Coumadin/warfarin therapy
* Patients with chronic orthopedic injury that might make them unable to participate in an exercise testing will also be excluded
* Subjects unable to speak English will not be recruited because of the complex experimental studies and the need for precise communication between the volunteers and the research staff to ensure safety.

Participant flow

Outcome results

• Cardiac Beta-receptor Sensitivity (Primary), Mean, beats per ng/kg/min ISO: Healthy Seniors 0.254 +/- 0.166; HFpEF 0.156 +/- 0.133; Healthy Young 0.365 +/- 0.129
• Central Command Regulation of Heart Rate (Primary), Mean, beats per minute: Healthy Seniors 93 +/- 11; HFpEF 89 +/- 14

Adverse events

Time frame: 2 years

• Results publication: Sarma S, Stoller D, Hendrix J, Howden E, Lawley J, Livingston S, Adams-Huet B, Holmes C, Goldstein DS, Levine BD. Mechanisms of Chronotropic Incompetence in Heart Failure With Preserved Ejection Fraction. Circ Heart Fail. 2020 Mar;13(3):e006331. doi: 10.1161/CIRCHEARTFAILURE.119.006331. Epub 2020 Mar 13. PMID 32164435

• Study Protocol (PDF, 2014-12-01)

• Benjamin D Levine, MD, Principal investigator, University of Texas Southwestern Medical Center