Cardiac Pulmonary Nerve Stimulation (CPNSTM): A Novel Treatment for Acute Decompensated Heart Failure.

Heart failure (HF) is a complex and devastating condition with well-defined long-term and irreversible complications. HF disease progression is marked by periods of worsening symptoms, otherwise known as acute decompensated heart failure (ADHF). Sadly, the current therapeutic approach for ADHF has remained the same for decades and has limitations associated with both patient safety and clinical effectiveness. Neuromodulation of the cardiac autonomic nerves is a novel therapeutic strategy hoping to address this unmet need for patients with HF.

The cardiovascular system is richly innervated with both sympathetic and parasympathetic fibers. Studies in human cadavers identified fibers responsible for the lusitropic and inotropic states of the ventricles that pass along the anterior and posterior surface of the right and main pulmonary arteries. Additional canine studies demonstrated stimulation in the pulmonary artery region leads to a selective increase in left ventricular (LV) contractility (measured by dP/dtmax) with no change in heart rate., Activating these nerves in close proximity to the heart allows for a localized effect without systemic consequences commonly seen with pharmacologic agents such as inotropes.

The Cardiac Pulmonary Nerve Stimulation (CPNSTM) System (Cardionomic, Inc) is a catheter-based investigational device designed to electrically stimulate the cardiac autonomic nerves surrounding the right pulmonary artery (RPA). The CPNS System has the potential to improve cardiac function (both inotropy and lusitropy), increase systemic perfusion, and enhance decongestion in ADHF using a temporary percutaneous device.

The CPNS System consists of the following:

Neuromodulation stimulation catheter (CN2 catheter) with a 16-electrode anchoring nitinol braid and 2 solid-state pressure sensors

Stimulator that delivers electrical current via the CN2 catheter and displays real-time electrocardiogram (ECG) and invasive pressure signals

ECG denoiser that receives ECG signals from the patient and passes ECG signals without stimulation artifacts to the hospital patient monitor and stimulator

The CN2 catheter is delivered percutaneously via the internal jugular vein using standard right heart catheterization techniques and fluoroscopic guidance into the target treatment location within the RPA. Once positioned, the CN2 catheter is deployed against the vessel wall to provide stimulation (Figure 1). Endovascular electrical stimulation is performed using a range of programmable stimulation parameters. An electric current is applied and adjusted based on the observed physiological response. Once a desirable response is achieved, the system can remain in place and provide therapy for up to 5 days. On completion of therapy, the CN2 catheter is completely removed and hemostasis of the venopuncture site is easily achieved.

Figure 1

CN2 Catheter Deployed in the RPA

The anchoring nitinol braid and 16-electrode array of the neuromodulation stimulation catheter (CN2 catheter) are positioned in the right pulmonary artery (RPA). Two integrated pressure sensors can be seen in the main pulmonary artery and right ventricle.

Initial clinical experience included a single-center, first-in-human proof-of-concept study that stimulated the cardiac pulmonary nerve through the RPA using commercially available electrophysiology mapping catheters. Fifteen subjects with an ejection fraction ≤35% on standard HF medications undergoing a planned implantation of either a cardiac resynchronization therapy device or a primary prevention implantable cardioverter-defibrillator were enrolled. Five subjects were not studied because of equipment failure or abnormal pulmonary artery anatomy. LV contractility (LV dP/dtmax) and mean arterial pressure increased by 22.6% ± 4.8% (P = 0.006) and 13.5% ± 3.8% (P = 0.006), respectively. There were no serious adverse events reported and no significant change in heart rate (4.0% ± 2.5%; P = 0.19) was observed. This study demonstrated that LV contractility and arterial blood pressure could be augmented without a significant change in heart rate in patients with HF.

The subsequent CPNS 2 Feasibility Study evaluated the short-term safety and feasibility of the novel CPNS System in patients with chronic HF who were undergoing a catheterization procedure or implantable cardioverter-defibrillator/cardiac resynchronization therapy implantation. Changes in LV contractility, arterial blood pressure, and heart rate were measured with and without stimulation over a period of 1-3 hours. Of the first 24 subjects enrolled, 18 patients underwent the stimulation procedure. Six patients were exited prior to study procedure because of screening failures. Of the 18 patients undergoing the procedure, 3 (17%) were nonresponders and 15 (83%) exhibited a response. In the 15 responders, LV dP/dtmax increased by an average of 60.3 ± 12.6% (P < 0.001) and mean arterial pressure increased by an average of 13.4% ± 3.8% (P < 0.001) while heart rate remained unchanged (1.0% ± 2.3%; P = 0.437). There were no device-related serious adverse events reported in this analysis. The study concluded that the CPNS System can reproducibly increase contractility with a neutral effect on heart rate while maintaining safety.

In summary, the CPNS System has demonstrated the ability to increase cardiac contractility without affecting heart rate via stimulation of cardiac nerves located along the RPA. This represents a novel therapy that may benefit patients with ADHF. Cardionomic is currently enrolling a global pilot study to evaluate the safety and performance of the CPNS System in patients hospitalized for ADHF (CPNS Pilot Study: Evaluation of Safety and Performance of the Cardiac Pulmonary Nerve Stimulation [CPNS] System in Patients With ADHF; NCT04814134).

All studies were conducted in compliance with human studies committees and regulatory agency guidelines, including patient consent where appropriate. All values are reported as mean ± SEM.