Safety Study of Pyridostigmine in Heart Failure
Safety Study of Pyridostigmine in Heart Failure
Heart failure, a common heart disease affecting nearly 6 million Americans, is associated
 with high rates of hospitalization and death. Abnormalities in the autonomic nervous system
 are thought to play an important role in the progression of heart failure. This proposal aims
 to determine whether novel application of pyridostigmine, a drug currently approved by the
 FDA only for the treatment of neuromuscular disease, can improve autonomic nervous system
 function in heart failure patients.
Autonomic dysregulation of the cardiovascular system, characterized by heightened sympathetic
 activity and withdrawal of parasympathetic activity promotes progression of heart failure.
 Pharmacological blockade of sympathetic overactivity is associated with reduced mortality
 risk, but there are few data on pharmacologic augmentation of parasympathetic withdrawal.
 Acetylcholinesterase inhibitors augment parasympathetic neurotransmission by blocking the
 enzymatic breakdown of acetylcholine at cholinergic receptor sites. Pyridostigmine is a
 short-acting, reversible acetylcholinesterase inhibitor approved by the FDA for the treatment
 of myasthenia gravis. Investigators propose a Phase II prospective randomized, double-blind
 trial to compare 12 weeks of treatment with ascending doses of pyridostigmine (15, 30, and 60
 mg every 8 hours) vs. matching placebo in 60 patients with symptomatic chronic heart failure
 associated with left ventricular systolic dysfunction.
Inclusion Criteria:

 -  Age 21-75 years

 -  Symptomatic NYHA Class II-III heart failure >6 months

 -  Left ventricular ejection fraction <35%

 -  Previous implantation of implantable cardiovertor defibrillator or pacemaker

 -  Guideline-recommended heart failure treatment for > 3 months

 -  Able and willing to provide written informed consent

 Exclusion Criteria:

 -  Contraindications to cholinergic stimulation

 -  Heart failure primarily attributable to genetic, valvular, infiltrative diseases

 -  Persistent atrial fibrillation

 -  Sick sinus syndrome

 -  Pacemaker dependency during exercise

 -  Severe chronotropic incompetence with peak exercise heart rate < 100 min-1

 -  Severe exercise intolerance (unable to complete first stage of Bruce Protocol)

 -  Coronary or cerebral atherothrombotic events within the past year

 -  Hospitalization of emergency room visit for heart failure within last 3 months

 -  ICD shock in last 6 months

 -  Diabetes mellitus with peripheral neuropathy

 -  Autonomic or peripheral neuropathy of any cause

 -  Systolic blood pressure <90 or >160 mmHg

 -  Resting heart rate <60 or >100 min-1

 -  Serum sodium < 132 mmol/L

 -  Serum creatinine >2.5 mg/dl

 -  Liver function tests >3 times upper limit of normal

 -  Severe anemia (Hemoglobin <10 gm/dl)

 -  FEV1.0 < 60% of predicted or FEV1.0/FVC ratio <70%

 -  PR interval >240 msec or second or third degree heart block on electrocardiogram

 -  Exercise limited primarily by angina or non-cardiac co-morbid condition

 -  Pregnant or breast-feeding women

 -  Current treatment with medications known to interact with pyridostigmine

 -  Known intolerance of oral preparations containing bromides

 -  Any condition (e.g., psychiatric illness or active substance abuse) or situation that,
 in the investigator's opinion, may put the subject at significant risk, may confound
 the study results, or may interfere significantly with the subject's ability to adhere
 with study procedures.