Ricardo Aviv

Cardiac Contractility Modulation by Electric Currents Applied During the Refractory Period in Patients With Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy

We assessed the feasibility of cardiac contractility modulation (CCM) by electric currents applied during the refractory period in patients with heart failure (HF). Extracellular electric currents modulating action potential and calcium transients have been shown to potentiate myocardial contractility in vitro and in animal models of chronic HF. CCM signals were biphasic square-wave pulses with adjustable amplitude, duration, and time delay from sensing of local electric activity. Signals were applied to the left ventricle through an epicardial vein (in 12 patients) or to the right ventricular (RV) aspect of the septum endocardially (in 6 patients). Simultaneous left ventricular (LV) and aortic pressure measurements were performed using a Millar catheter (Millar Instruments, Houston, Texas). Hemodynamics during RV temporary dual-chamber pacing was regarded as the control condition. Both LV and RV CCM stimulation increased dP/dt(max) to a similar degree (9.1 +/- 4.5% and 7.1 +/- 0.8%, respectively; p <0.01 vs controls), with associated aortic pulse pressure changes of 10.3 +/- 7.2% and 10.8 +/- 1.1% (p <0.01 vs controls). Regional systolic wall motion assessed quantitatively by color kinesis echocardiography was markedly enhanced near the CCM electrode, and the area of increased contractility involved 4.6 +/- 1.2 segments per patient. In 6 patients with HF with left bundle branch block, CCM signals delivered during biventricular pacing (BVP) produced an additional 16.1 +/- 3.7% increase in dP/dt(max) and a 17.0 +/- 7.5% increase in pulse pressure compared with BVP alone (p <0.01). CCM stimulation in patients with HF enhanced regional and global measures of LV systolic function, regardless of the varied delivery chamber or whether modulation was performed during RV pacing or BVP.

One-Year Experience with Tantalus™: a New Surgical Approach to Treat Morbid Obesity

Background: Increased caloric density in modern processed foods may be an important factor underlying the prevalence of obesity, because low-volume, high-caloric food intake may delay activation of volume-dependent gastric mechanical activity known to induce the feeling of fullness. We therefore hypothesized that enhancement of gastric contractions by electrical stimulation at an early stage of the meal will reduce food intake and body weight in morbidly obese subjects. Methods: The study was a prospective, non-randomized, open-label, single-center trial. 12 subjects (age 36.1 ± 2.8 years, BMI 43.2 ± 2.7 kg/m2, weight 128.8 ± 5.2 kg, means±SEM) underwent laparoscopic implantation with the Tantalus™ system. A pulse generator with 3 bipolar leads was implanted: 2 pairs in the antrum and a 3rd pair in the fundus. The system was activated at week 6. All subjects were followed for 20 weeks and 9 of them for 52 weeks. Results: All subjects finished the initial 20-week observation period. Following activation of the Tantalus™ System, a reduction (P<0.05) in hunger and an increase in cognitive control (P<0.05) as assessed by the Three-Factor Eating Questionnaire (TFEQ) could be observed. Body weight decreased (P<0.05) from 128.8±5.2 to 119.9+5.9 (17.6+4.3% EWL, N=12) after 20 weeks (14 weeks of treatment). In the 9 subjects continuing for 52 weeks (46 weeks of treatment), body weight further decreased to 112.4 ± 3.8 kg (26.6 ± 8.5 %EWL, N=9). Blood pressure decreased (P<0.05) from 142 ± 6.1/91 ± 3.2 to 125.5 ± 4.0/83 ± 2.6 mmHg by week 20 and 128.8 ± 3.8 / 86.3 ± 3.6 mmHg after 1 year. The frequency and severity of device and/or procedure-related adverse events indicate that the method is safe and well-tolerated. Conclusion: This data suggests that gastric stimulation by the minimally invasive Tantalus™ System is safe and leads to favorable changes in eating behavior, clinically significant weight loss and reduction in blood pressure. Treatment with the Tantalus™ System is therefore a promising minimally invasive treatment for obesity.

Cardiac contractility modulation with the impulse dynamics signal: studies in dogs with chronic heart failure.

The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure is limited by pro-arrhythmic and positive chronotropic effects. Chronic use of these agents, while eliciting an improvement in the quality of life of patients with advanced heart failure, has been abandoned because of marked increase in mortality when compared to placebo. Nevertheless, patients with advanced heart failure can benefit from long-term positive inotropic support if the therapy can be delivered ‘on demand’ and in a manner that is both safe and effective. In this review, we will examine the use of a novel, non-stimulatory electrical signal that can acutely modulate left ventricular (LV) contractility in dogs with chronic heart failure in such a way as to elicit a positive inotropic support. Cardiac contractility modulation (CCM) with the Impulse Dynamic™ signal was examined in dogs with chronic heart failure produced by intracoronary microembolizations. Delivery of the CCM signal from a lead placed in the great coronary vein for periods up to 10 minutes resulted in significant improvements in cardiac output, LV peak+dP/dt, LV fractional area of shortening and LV ejection fraction measured angiographically. Discontinuation of the signal resulted in a return of all functional parameters to baseline values. In cardiomyocytes isolated from dogs with chronic heart failure, application of the CCM signal resulted in improved shortening, rate of change of shortening and rate of change of relengthening suggesting that CCM application is associated with intrinsic improvement of cardiomyocyte function. The improvement in isolated cardiomyocyte function after application of the CCM signal was accompanied by an increase in the peak and integral of the Ca2+ transient suggesting modulation of calcium cycling by CCM application. In a limited number of normal dogs, intermittent chronic delivery of the CCM signal for up to 7 days showed chronic maintenance of LV functional improvement. In conclusion, pre-clinical results to date with the Impulse Dynamics CCM signal indicate that this non-pharmacologic therapeutic modality can provide short-term positive inotropic support to the failing heart and as such, may be a useful adjunct in the treatment of advanced heart failure. Additional, long-term studies in dogs with heart failure are needed to establish the safety and efficacy of this therapeutic modality for the chronic treatment of this disease syndrome.

Electrical modulation of cardiac contractility: Clinical aspects in congestive heart failure

Heart failure is a highly prevalent disease in western society. Drug therapies aimed at increasing myocardial contractility have been associated with decreased survival. Several short and mid term clinical studies have suggested adjuvant or alternative therapies to congestive heart failure using modified pacing techniques that were aimed to increase contractility (e.g. Paired pacing) or restore synchrony of contraction (biventricular pacing). While delivery of paired pacing was abandoned during the early 70s, biventricular pacing has recently emerged as an adjuvant treatment to limited group of congestive heart failure patients with aberrant left ventricular conduction. In this brief review, we describe our initial safety and efficacy experience in patients with heart failure using a novel non-stimulatory electrical approach to the delivery of positive inotropic therapy to the failing myocardium. The study suggests that unlike modified pacing techniques, delivery of the signal to the left ventricle during the refractory period resulted in a rapid increase in myocardial contractility and improved hemodynamic performance. The near instantaneous contractility improvement achieved by this type of stimulus was shown to be safe and effective independently of the primary cause of heart failure or the function of the conduction system. Unlike pharmacologic treatments, which have a relatively constant effect, use of electrical stimuli may prove useful as a new therapeutic modality in the treatment of heart failure with which contractility can be improved when and as needed.

Association between Gastric Electromechanical Activity and Satiation in Dogs

Objective: The objective of this study was to validate the use of impedance for measurement of antral contractions and to determine the relationship between food‐induced changes in gastric motility and satiation.

Global Improvement in Left Ventricular Performance Observed with Cardiac Contractility Modulation is the Result of Changes in Regional Contractility

Cardiac Contractility Modulation (CCM) is a novel therapeutic strategy for increasing myocardial systolic performance. CCM involves nonexcitatory electrical stimulation that can be delivered via standard LV pacing lead approaches (i.e. temporary epicardial electrodes placed during surgery or specialized coronary venous leads presently under development). Unlike other heart failure therapies, CCM is targeted to a very speci®c region of the myocardium, thus avoiding extracardiac side effects and untoward effects related to nonspeci®c cardiac activation. The purpose of this paper is to review experiments performed for the most part in normal, acute experimental preparations, that assess the spatial extent of the CCM effect. These experiments support the hypothesis that the global effects on cardiac systolic function observed during CCM are the direct result of changes in regional contractility close to the CCM site. The implications of this observation, including the possibility of taking advantage of potential regional differences in susceptibility to CCM effect or optimizing therapy by multisite CCM stimulation will also be discussed.

Complete adaptation to chronic potassium loading after adrenalectomy: possible humoral mechanisms.

This study was designed to evaluate the mechanisms of adaptation to chronic potassium loading after bilateral adrenalectomy. Studies were performed in Sprague-Dawley rats subjected to 3 days of normal diet and 9 days of high KCl diet followed by adrenalectomy or sham operation on the thirteenth day and 9 additional days of potassium loading (groups 1 and 2, respectively). Animals that underwent adrenalectomy and intact animals, both receiving a normal diet, served as the control groups (groups 3 and 4, respectively). Plasma potassium, urinary potassium and sodium excretion rates, plasma aldosterone and insulin, and Na+-K+ ATPase activity in renal cortical and medullary homogenates were measured. Within 5 days of adrenalectomy the urinary potassium excretion rate in potassium-loaded rats that underwent adrenalectomy (group 1) reached the level observed in potassium-loaded intact rats (group 2), but a significant elevation in plasma potassium levels among rats in group 1 was noticed. In both of the potassium-loaded groups plasma insulin levels and renal cortical and medullary Na+-K+ ATPase activity were significantly higher compared with those in respective control groups receiving a normal diet. Acute clearance experiments carried out in adrenalectomized rats infusing the sera of the potassium-adapted rats that underwent adrenalectomy (obtained at the end of the chronic experiment) showed an uprise in urinary potassium excretion. This result was not observed after the infusion of control sera. These findings suggest that full renal adaptation to chronic potassium loading can be achieved in the absence of aldosterone through mechanisms that might be related to elevated plasma insulin levels (extrarenal); also, a humoral factor associated with the renal adaptation cannot be ruled out.