Novel Neuromodulation Approach to Improve Left Ventricular Contractility in Heart Failure: A First-in-Human Proof-of-Concept Study.

BACKGROUND: Morbidity and mortality outcomes for patients admitted for acute decompensated heart failure are poor and have not significantly changed in decades. Current therapies are focused on symptom relief by addressing signs and symptoms of congestion. The objective of this study was to test a novel neuromodulation therapy of stimulation of epicardial cardiac nerves passing along the posterior surface of the right pulmonary artery. METHODS: Fifteen subjects admitted for defibrillator implantation and ejection fraction ≤35% on standard heart failure medications were enrolled. Through femoral arterial access, high fidelity pressure catheters were placed in the left ventricle and aortic root. After electro anatomic rendering of the pulmonary artery and branches, either a circular or basket electrophysiology catheter was placed in the right pulmonary artery to allow electrical intravascular stimulation at 20 Hz, 4 ms pulse width, and ≤20 mA. Changes in maximum positive dP/dt (dP/dtMax) indicated changes in ventricular contractility. RESULTS: Of 15 enrolled subjects, 5 were not studied due to equipment failure or abnormal pulmonary arterial anatomy. In the remaining subjects, dP/dtMax increased significantly by 22.6%. There was also a significant increase in maximum negative dP/dt (dP/dtMin), mean arterial pressure, systolic pressure, diastolic pressure, and left ventricular systolic pressure. There was no significant change in heart rate or left ventricular diastolic pressure. CONCLUSIONS: In this first-in-human study, we demonstrated that in humans with stable heart failure, left ventricular contractility could be accentuated without an increase in heart rate or left ventricular filling pressures. This benign increase in contractility may benefit patients admitted for acute decompensated heart failure.

Pressure gradients in the brain in an experimental model of hydrocephalus.

OBJECT: The goal of this investigation was to establish whether pressure gradients exist between the ventricles, brain tissue, and subarachnoid space when acute or chronic hydrocephalus develops. Such gradients are hypothesized by many models of hydrocephalus, but considerable controversy continues about their existence. METHODS: A stereotactic frame was used for surgery in dogs to implant pressure sensors within the right lateral ventricle, the frontal lobe, and forward in the subarachnoid space. The dogs were allowed to recover for 10 to 14 days postoperatively. Then, 800 mg of sterile kaolin in water was injected into the cisterna magna region by using a percutaneous approach. Both real-time and long-term intracranial pressures were measured. Of the six dogs, one experienced an intracranial hemorrhage, one dog displayed status epilepticus after a second injection of kaolin and was killed, one experienced acute hydrocephalus, and three experienced mild chronic hydrocephalus. No consistent pressure differences were found in any dog between the ventricle, brain, and subarachnoid space before kaolin administration or afterward when hydrocephalus developed. In addition, no pulse pressure gradients occurred between the brain and the ventricle or subarachnoid space. CONCLUSIONS: Precise monitoring of pressure before and during the development of hydrocephalus did not detect pressure gradients between the ventricle, brain, and subarachnoid space. This was true for long-term measurements over weeks and for real-time measurements that allowed accurate assessment of pulse pressures. Theories predicting pressure gradients greater than the resolution of these sensors (0.5 mm Hg) across brain tissue have to be reevaluated in light of these findings.

Feasibility of using an implantable system to measure thoracic congestion in an ambulatory chronic heart failure canine model.

BACKGROUND: Noninvasive measures of impedance reflect alterations in thoracic fluid and pulmonary edema in acute animal and human studies. MATERIALS AND METHODS: We evaluated the feasibility of using an implantable impedance measuring device and cardiac lead system to monitor intrathoracic congestion in a pacing-induced heart failure canine model. Three devices were implanted in each of five dogs: a modified pacemaker to measure impedance from a defibrillation lead implanted in the right ventricle; an implantable hemodynamic monitoring device to measure left ventricular end diastolic pressure (LVEDP) and a second pacemaker to deliver rapid (240 pulses per minute) ventricular pacing to induce heart failure. RESULTS: All five dogs developed severe heart failure after 3-4 weeks of rapid pacing and recovered following pacing termination. The LVEDP increased and impedance decreased during pacing-induced heart failure and recovered after pacing cessation. At the end of pacing, there was a mean impedance reduction of 10.6 +/- 8.3% and a mean LVEDP increase of 18.1 +/- 4.5 mmHg compared to baseline. The impedance and LVEDP were inversely correlated (r =-0.41 to -0.85, all P < 0.05). CONCLUSIONS: In the canine model, measurement of chronic intrathoracic impedance with an implantable system effectively revealed changes in thoracic congestion due to heart failure reflected by LVEDP. These data suggest that implantable device-based impedance measurement merits further investigation as a tool to monitor the fluid status of heart failure patients.

Detection of acute myocardial ischemia during percutaneous transluminal coronary angioplasty by endocardial acceleration.

The first heart sound is generated by vibrations from the myocardium during isovolumic contraction. Peak endocardial acceleration (PEA) has been used previously to measure these vibrations in humans and correlates with myocardial contractility during inotropic interventions. It is unknown if changes in PEA can be used to characterize a reduction in contractility during ischemic episodes. This study was designed to evaluate the use of an endocardial accelerometer for the detection of acute myocardial ischemia. Thirteen patients undergoing routine percutaneous transluminal coronary angioplasty (PTCA) consented to having a single-axis, lead-based accelerometer positioned in the right ventricular apex. PEA was defined as the maximum peak-to-peak amplitude during a window 50 ms before to 200 ms following the peak R wave. Time of endocardial acceleration (TEA) was defined as the time from the peak R wave to the maximum accelerometer signal within this window. To obtain a more robust estimate of the strength of vibrations, a 100-beat template of the accelerometer signal was constructed at baseline and applied as a matched filter during ischemia. The peak magnitude of the filtered endocardial accelerometer signal (Max Filtered EA) was used as an index of signal intensity. Median baseline PEA, TEA, and Max Filtered EA were 0.91 +/- 0.35 g, 75.2 +/- 16.2 ms, and 0.40 +/- 0.20 g, respectively. PEA and Max Filtered EA significantly decreased by 7% during ischemia (0.91 to 0.85 g and 0.40 to 0.37 g, both P < 0.05, respectively). TEA did not significantly change from baseline (77.0 ms, P = ns). The results of this study suggest that acute ischemia can be detected with an endocardial accelerometer in humans.

Comparison of electrocardiogram and intrathoracic electrogram signals for detection of ischemic ST segment changes during normal sinus and ventricular paced rhythms.

INTRODUCTION: The aim of this study was to compare surface ECGs with electrograms (EGM) that are available from implanted devices for the ability to detect ischemic ST segment changes during normal sinus (NS) and ventricular paced (VP) rhythms. METHODS AND RESULTS: ECG leads I, II, and V2, right atrial ring to left pectoral patch (representing the can of the device), right ventricular ring to left pectoral patch, and right atrial ring to right ventricular ring EGM were recorded continuously during percutaneous transluminal coronary angioplasty. One balloon inflation (> or = 60 sec) was analyzed from each of 22 NS and 22 VP subjects. The parameter AST was defined as the maximum absolute ST segment deviation (from isoelectric) during the first 60 seconds of inflation, measured relative to the baseline (preinflation) ST segment deviation. For EGM, a normalized deltaST was defined as the AST divided by the ratio of QRS amplitudes of EGM to ECG. During NS, the deltaST for EGM (0.43 mV) was significantly larger than that of ECG (0.09 mV, P = 0.0001) but the normalized deltaST for EGM (0.11 mV) was comparable to that of ECG (0.09 mV, P = 0.45). During VP, the AST for EGM (1.08 mV) was significantly larger than that of ECG (0.17 mV, P = 0.0001), but the normalized AST for EGM (0.11 mV) was significantly smaller than that of ECG (0.17 mV, P = 0.02). CONCLUSION: During both NS and VP, ischemic ST segment changes were significantly larger in EGM than in ECG. Much of this difference appears to be related to larger amplitudes of EGM signals. (J