Evaluation of the Safety and Efficacy of the 2-lead OPTIMIZER® Smart System

This is a multicenter, prospective, single-arm treatment only confirmatory study of the
2-lead configuration of the Optimizer Smart System.

Inclusion Criteria:

- Subjects who are 18 years of age or older

- Subject is male or a non-pregnant female

- Subjects who have a baseline ejection fraction greater than or equal to 25% and less
than or equal to 45% by echocardiography determined by the echocardiography core
laboratory.

- Subjects who have been treated for heart failure for at least 90 days (including
treatment with a β-blocker for at least 90 days unless the subject is intolerant) and
are in New York Heart Association functional Class III and IV at the time of
enrollment.

- Subjects receiving appropriate, stable medical therapy during the 30 days prior to
enrollment for treatment of heart failure according to guideline recommendations. For
patients with EF≤35%, this regimen shall consist of the appropriate doses of
diuretics, ACE-inhibitor or angiotensin II receptor blocker and β-blocker. Angiotensin
receptor -neprilysin inhibitor (ARNI) may be substituted for ACE inhibitors or ARBs
and Ivabradine may also be considered in subjects with a heart rate >70bpm. Stable is
defined as no more than a 100% increase or 50% decrease in dose.

- Subjects who, in the opinion of the Principal Investigator (based on the current
guidelines for clinical practice), have a clinical indication for an implanted cardiac
defibrillator (ICD, e.g., EF≤35%) and/or pacemaker, must have an existing device
unless the patient refuses to undergo the implantation of such device for personal
reasons.

- Subjects who are willing and able to return for all follow-up visits.

Exclusion Criteria:

- Subjects whose baseline peak VO2 is <9 or >20 ml O2/min/kg. The qualifying CPX test
must be deemed adequate.

- Subjects who have a potentially correctible cause of heart failure, such as valvular
heart disease or congenital heart disease.

- Subjects who have clinically significant angina pectoris, consisting of angina during
daily life (i.e., Canadian Cardiovascular Society Angina score of II or more), an
episode of unstable angina within 30 days before enrollment, or angina and/or ECG
changes during exercise testing performed during baseline evaluation.

- Subjects hospitalized for heart failure requiring acute treatment with intravenous
loop diuretics, IV inotropes or hemofiltration within 30 days before enrollment and
baseline testing or subjects receiving any form of positive inotropic support within
30 days before enrollment, including continuous IV inotrope therapy.

- Subjects having a PR interval greater than 375ms.

- Subjects whose exercise tolerance is limited by a condition other than heart failure
(e.g., angina, COPD, peripheral vascular disease, orthopedic or rheumatologic
conditions) or who are unable to perform baseline stress testing.

- Subjects who are scheduled for a CABG or a PTCA procedure, or who have undergone a
CABG procedure within 90 days or a PTCA procedure within 30 days of enrollment.

- Subjects who have a biventricular pacing system, an accepted indication for such a
device, or a QRS width of 130ms or greater.

- Subjects who have had a myocardial infarction within 90 days of enrollment.

- Subjects who have mechanical tricuspid valve.

- Subjects who have a prior heart transplant.

- Subjects on dialysis.

- Subjects who are participating in another experimental protocol.

- Subjects who are unable to provide informed consent.