PITA-HF: Feasibility, Safety, and Tolerability

Overview

Heart failure affects over 25 million people worldwide and nearly 7 million adults in the United States alone. Nearly 25% of patients with heart failure have worsened disease burden from dyssynchronous ventricular contraction due to abnormal electrical impulse propagation. These patients may benefit from cardiac resynchronization therapy (CRT) where contraction between the ventricles is coordinated by simultaneous electrical stimulation of the right and left ventricles. In animal models, CRT changes molecular and cellular biology by improving myofilament function, ion channel regulation, beta-receptor signaling, and overall mitochondrial energetics. In randomized clinical outcomes trials, the use of CRT further reduced the incidence of heart failure events and improved overall mortality. However, nearly 75% of patients with heart failure have synchronous ventricular contraction and therefore do not qualify for CRT. CRT profoundly alters underlying molecular and cellular biology as a result of the transition from dyssynchronous to resynchronized contraction, enhancing myocyte function and adrenergic responsiveness. The investigators previously hypothesized CRT-like benefits could be achieved in otherwise synchronous heart failure by purposely inducing dyssynchrony for several hours each day and then reversing this for the remainder of the time. The investigators termed this pacemaker induced transient dyssynchrony, or PITA, and tested its impact in a canine dilated cardiomyopathy model. Following several weeks of rapid atrial pacing to induce heart failure in the animals, the investigators compared implementing 4-weeks of PITA - consisting of dyssynchronous rapid right ventricular pacing for 6 hours each night and atrial pacing for the remaining time - to animals that always received rapid atrial pacing. The fast rate is used to generate a heart failure phenotype. PITA improved chamber dilation, increased beta-adrenergic responsiveness and contractile function, and improved myofiber structure compared to heart failure canine controls. While first tested in an intact conscious translational model, no study has yet investigated PITA in humans. This pilot research protocol tests the feasibility, safety, and tolerability of PITA in humans with dilated cardiomyopathy. The study will leverage pre-existing Medtronic (Mounds View, MN) pacemaker/defibrillators implanted in dilated cardiomyopathy patients based on current clinical guidelines. If successful, this study will allow for a larger, first-in-human study to assess indexes of left ventricular function in dilated cardiomyopathy patients with PITA.

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.