Chronotropic Incompetence in Patients With HFpEF
Condition: Heart Failure
MeSH terms: Heart Failure
Study type: Interventional

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".
    

Intervention name(s): Static Handgrip; Dexmedetomidine; Glycopyrrolate; Isoproterenol
Intervention type(s): Other; Drug; Drug; Drug
Intervention description(s): Subjects will perform static handgrip at 40% of maximum voluntary contraction until fatigue.; 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.; 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.; 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.
Other intervention name(s): Sympathetic blockade; Parasympathetic blockade; Beta-receptor sensitivity testing
Intervention MeSH terms: Isoproterenol; Glycopyrrolate; Dexmedetomidine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science