Over 25 million people worldwide are affected by heart failure. In the United States alone,
nearly 7 million adults have heart failure with a prevalence of ~3% of adults over 18 years
old. Therapy is directed at the underlying cause of heart failure and stratified by ejection
fraction. In patients with heart failure with reduced ejection fraction (HFrEF), standard
guideline-directed medical therapy consists, at minimum, of maximally tolerated beta blockade
and angiotension converting enzyme (ACE) inhibitor or angiotension receptor blockade (ARB)
therapy. Additive therapies may include further neurohormonal blockade with spironolactone or
eplerenone, with symptomatic management anchoring on lifestyle modifications and diuretics.
Antiarrhythmic devices are commonly employed in HFrEF patients. Patients with ischemic heart
disease and an ejection fraction below 35% are recommended for internal cardiac
defibrillators (ICD) as primary prevention, and those who have experienced episodes of sudden
cardiac arrest or syncope related to ventricular arrhythmia are candidates for ICDs as
secondary prevention. Individuals with non-ischemic HFrEF are recommended for secondary
prevention ICD implantation.
Another device therapy is cardiac resynchronization therapy (CRT) used in HFrEF patients with
underlying delayed electromechanical conduction delay. With differences in regional
electrical propagation as with left bundle branch blocks or intraventricular conduction
delays, the left ventricular free wall and septum (left and right sides) contract in a
discoordinate manner, reducing overall pump efficiency and mechanoenergetic performance. CRT
employs pacing of the left ventricular lateral wall and right ventricular septum
simultaneously, recoordinating electromechanical activation to improve ventricular function.
The investigators previously showed that while CRT improves chamber-level mechanoenergetics,
it also results in profound molecular and myocyte changes that are often global in nature and
underlie functional improvement. In a dilated cardiomyopathy canine model (rapid pacing for 6
weeks), CRT improves myofilament function, ion channel regulation, beta-receptor signaling,
and mitochondrial function and energetics. Several of these features have been examined in
human endocardial biopsies following CRT supporting the appearance of these features in
patients.
Furthermore, in large-scale, randomized trials, CRT improved cardiovascular outcomes. The
MIRACLE trial randomized 453 patients to CRT with EF <35% and QRS >130 ms to CRT vs control
and found significant improvements in clinical endpoints of six minute walk distance,
functional class, quality of life, and ejection fraction. The COMPANION trial randomized
1,520 patients with advanced heart failure and intraventricular conduction delays to standard
medical therapy, CRT-P (pacemaker only), or CRT-D (defibrillator). In both CRT groups, there
were significant reductions in the primary endpoint of time to death or hospitalization, with
relative reductions of 34% and 40% respectively. The MADIT-CRT trial randomized 1,820
patients with ejection fraction <30% and QRS duration of >130 milliseconds with New York
Heart Association class I or II symptoms to CRT-D or ICD therapy alone. In the CRT-D group, a
significant reduction in the primary endpoint of death from any cause or nonfatal heart
failure event was observed. Interestingly, the Echo CRT trial randomized 809 patients with
ejection fraction <35%, QRS <130 milliseconds, and New York Heart Association class III or IV
heart failure with echocardiographic evidence of left ventricular dyssynchrony to CRT vs dual
chamber pacemaker. Unlike MADIT-CRT, there was no significant differences in the primary
endpoint of death or first hospitalization for worsening heart failure between the groups
prompting the trial to terminate early, suggesting that the benefit from CRT is contingent
upon high baseline level of ventricular dyssynchrony. Based on MADIT-CRT and other
large-scale trials, CRT is now recommended as per the recent American College of
Cardiology/American Heart Association heart failure guidelines as Class I indication in
patients with (1) New York Heart Association (NYHA) Class III or IV symptoms despite optimal
heart failure therapy with left ventricular ejection fraction (LVEF) <35% and prolonged QRS
duration or (2) NYHA Class I, II, or III symptoms with LVEF <50% on optimal heart failure
therapy with expected high percentage of ventricular pacing.
Despite the success of CRT as additive therapy, it is limited to a subset of heart failure
patients with a wide QRS complex and evidence of mechanical dyssynchrony. The majority of
patients (~75%) with HFrEF have synchronous ventricular contraction with narrow QRS complexes
on surface ECGs and so do not qualify for CRT. However, the molecular/cellular biology
following CRT raised a provocative question: might purposely inducing dyssynchrony in heart
failure for a discrete period of time and then reversing it also confer similar benefits to
CRT? This notion of purposely applying a stimulus that if done for a prolonged period has
adverse impact but more short term and then reversed yields therapeutic benefit has an
analogy to ischemic pre-conditioning, where brief exposure to ischemia and then reperfusion
instills protective molecular changes to better handle subsequent prolonged ischemic injury.
To test this hypothesis, the investigators first tested the effects of pacemaker-induced
transient dyssynchrony (termed PITA) in a dilated cardiomyopathy canine model. After 2-weeks
of synchronous atrial tachypacing at 200 beats per minute to induce dilated cardiomyopathy,
dogs were exposed to PITA consisting of dyssynchronous (with respect to atrial contraction)
right ventricular pacing at the same rate from midnight to 6 AM each day, corresponding to
the period of least activity. Pacing was switched to rapid atrial pacing (same rate) for the
rest of the day: 6 AM to midnight. A control group of dogs received rapid atrial pacing only.
Indices of global left ventricular function and cellular/molecular changes were compared
between the groups and to controls without heart failure. The investigators found that intact
left ventricular chamber end diastolic and end systolic diameters were smaller and ejection
fraction greater in dogs receiving PITA. Left ventricular end diastolic pressure was
decreased in the PITA group versus HF controls. Left ventricular contractility also improved
in the PITA group, primarily with co-administered dobutamine to stimulate contractile
reserve. The latter ultimately achieved levels similar to those in healthy controls, so the
adrenergic response improvement was substantial. Thus, PITA attenuated adverse remodeling due
to synchronous HF in the intact heart.
At the myocyte level, PITA improved sarcomere shortening, peak calcium transient, myofilament
sarcomere function (peak myocyte force-calcium dependence), and beta adrenergic stimulated
response (both b1 and b2). Ultrastructurally, PITA preserved myofilament assembly and
integrity, and prevented the formation of low-force generating myofibrils. Interestingly, all
of these beneficial effects of PITA were only seen when a contiguous period of right
ventricular (RV) pacing was applied. When RV pacing was randomly distributed over a 24-hour
period, no significant mechanoenergetic or cellular/molecular differences were seen between
the treated and control HF groups.
To date, no study has investigated whether similar benefits of PITA are observed in humans
with HFrEF. PITA can be easily implemented in HFrEF patients with primary or secondary
prevention ICDs or pacemakers inserted to counter bradycardia. Not all pacemaker devices can
currently do this, but multiple Medtronic (Mounds View, MN) devices have what is called a
Sleep Function feature whereby the pacing rate can be automatically modified during
predefined sleep periods, generally lowering this rate so a slower intrinsic non-paced rate
occurs. While incorporated to help some patients who felt hearts beat when the patients
slept, the feature is in fact rarely used. However, the software has the capacity to be
inverted - where the "sleep period" is set to extend from 6 AM to midnight, and then the
daytime (faster backup pacing rate) occurs from midnight to 6 AM. The investigators can then
pace the RV at a rate that is ~10 bpm above the upper sinus rate observed during the normal
sleep hours in a given patient, assuring that there will be dyssynchronous contraction during
those hours. In the morning, the rate would fall to below sinus rate to enable normal
contraction (synchronous) to be restored.
Given the increasing incidence and prevalence of HFrEF with associated morbidity and
mortality, it is important to find additional avenues to intervene and provide beneficial
therapies in addition to established medical therapy. While synchronous contraction is a
sought-after goal for patients with HFrEF, PITA may be even better and provide an additional
device-based therapy to improve heart failure symptoms and overall trajectory in those who
already have cardiac defibrillators or meet indications for implantation. Thus, further
investigation of the efficacy and safety of these treatments in the HFrEF population without
known dyssynchrony is warranted.
This index pilot trial will test the feasibility, safety, and tolerability of PITA in dilated
cardiomyopathy patients with low pacing burden to ensure ventricular capture during RV pacing
and to enroll patients who otherwise do not meet criteria for CRT. If successful, this will
allow subsequent study on changes in left ventricular function.
