Improvement in glycemic control in morbidly obese type 2 diabetic subjects by gastric stimulation.

BACKGROUND: Gastric electrical stimulation synchronized to the refractory period of gastric electrical activity and applied during meals was evaluated for safety and for improvement of body weight and glycemic control in obese type 2 diabetes. METHODS: The study involved obese diabetic type 2 (ODM) patients in a multicenter open-label European feasibility trial. A total of 24 ODM (nine males, 15 females) treated with insulin and/or oral hyperglycemic agents and body mass index between 33.3 to 49.7 kg/m(2) were implanted laparoscopically with a TANTALUS system. RESULTS: There were 18 adverse events related to the implant procedure or the device reported in 12 subjects. All were short lived and resolved with no sequelae. In the 21 subjects that reached the 1-year visit weight was reduced by 4.5 +/- 2.7 kg (p < 0.05) and HbA1c by 0.5 +/- 0.3% (p < 0.05). In a subgroup (n = 11) on stable or reduced oral medication, weight was reduced by 6.3 +/- 3.4 kg (p < 0.05) and HbA1c by 0.9 +/- 0.4% (p < 0.05). The group on insulin (n = 6) had no significant changes in weight and HbA1c. CONCLUSIONS: The TANTALUS system is well tolerated in obese type 2 diabetic subjects. Gastric electrical stimulation can potentially improve glucose metabolism and induce weight loss in obese diabetic patients, who are not well controlled on oral antidiabetic therapy. Further evaluation is required to determine whether this effect is due to induced weight loss and/or to direct signal dependent mechanisms.

Rationale and evidence for the development of a durable device-based cardiac neuromodulation therapy for hypertension.

We assessed the feasibility of achieving acute, sustained blood pressure reductions through the use of cardiac pacing algorithms delivered via standard dual-chamber pacing based on introducing short atrio-ventricular (AV) delays (SAVD). Eighteen hypertensive subjects (57.3 ± 9.8 years old; 10 male and 8 female) with average initial systolic and diastolic blood pressures of 151.2 ± 17.6/92.2 ± 12.7 mmHg already scheduled to undergo an invasive electrophysiology procedure were included in this study. Pacing sequences were applied for ∼1-minute intervals with AV delays of 80, 40, 20 and 2 ms, while making high fidelity blood pressure measurements. Average reductions of 19.6 ± 7.7 mmHg in systolic pressure and 4.3 ± 3.8 mmHg in diastolic pressure (P < .001 each) were demonstrated with 2 ms AV delay pacing. Initial SBP reductions were followed by rebound effects which diminished the SBP reducing effects of SAVD pacing, likely due to baroceptor activation causing increased peripheral resistance. This effect was eliminated by intermittent introduction of longer AV delay pacing which modulated the baroreflexes. These findings provide the rationale and evidence underlying recent data showing significant and long-term blood pressure reductions in response to this cardiac neuromodulation therapy in hypertensive patients despite medical therapy.

The TANTALUS system for obesity: effect on gastric emptying of solids and ghrelin plasma levels.

BACKGROUND: Gastric electrical stimulation (GES), using the implantable TANTALUS System, is being explored as a treatment for obesity. The system delivers nonstimulatory electrical signals synchronized with gastric slow waves, resulting in stronger contractions. We hypothesized that this GES may enhance gastric emptying and as a result affect plasma ghrelin and insulin homeostasis. The aim was to test the effect of GES on gastric emptying of solids and on ghrelin and insulin blood levels in obese subjects. METHODS: The system consists of 3 pairs of gastric electrodes connected to an implantable pulse generator. Gastric emptying test (GE) of solids was performed twice, on separate days, a few weeks after implantation, before and after initiation of stimulation. Blood samples for ghrelin and insulin were taken at baseline and at 15, 30, 60 and 120 min after the test meal. RESULTS: There were 11 females, 1 male, mean age 39.1 +/- 8.9 years, mean BMI 41.6 +/- 3.4. Data is available from 11 subjects; GE was normal in 9 subjects and accelerated in 2 subjects. GES significantly accelerated GE compared to control: percent retention at 2 hours 18.7 +/- 12.2 vs 31.9 +/- 16.4, respectively (P < 0.01). Overall, there was no significant change in ghrelin or insulin profile after food intake. Ghrelin levels fell significantly at 60 min compared to baseline during stimulation (P = 0.014) and control (P = 0.046). CONCLUSION: GES results in a significant acceleration of gastric emptying of solids in obese subjects. GES did not have a significant effect on postprandial ghrelin levels when compared to control.

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/m(2), 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 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.

Electrical stimulation of the gut for the treatment of type 2 diabetes: the role of automatic eating detection.

BACKGROUND: Automatic eating detection (AED) can potentially support treatments that need to be synchronized with food intake. This article analyzes an implantable AED device working in conjunction with gastric stimulation intended to treat type 2 diabetes (T2DM). The device continuously senses for changes in tissue impedance and electrical activity induced by food intake and initiates treatment sessions upon detection. This article reviews AED performance as well as its relevance to treatment outcomes. METHODS: Obese T2DM (n = 12) were implanted with gastric leads and the TANTALUS device. An AED algorithm was embedded in the device and was used to initiate periods of electrical stimulation during food intake. AED performance was assessed using patients' food diaries. The treatment outcome at 37 weeks postimplants was correlated with the rates of stimulation during large meals vs stimulation during periods of no caloric intake. RESULTS: The algorithm was able to detect 73% of meals consumed while sensing. The rate of false stimulations was 28%. Stimulation during meals was significantly correlated (R(2) = 0.45, p < 0.05) with hemoglobin A1c change (average drop in hemoglobin A1c was -1 +/- 0.4%) but not with changes in body weight (average drop -4.7 +/- 2.8 kg). Stimulation during periods with no caloric intake was negatively correlated with hemoglobin A1c reduction (R(2) = 0.27, p < 0.05). CONCLUSIONS: Sensing of gastric activity can be used for detection of food intake. The synchronization of gastric stimulation to periods of food intake is correlated with metabolic outcomes. AED may also benefit other applications such as drug delivery and control of food restriction devices.

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. RESEARCH METHODS AND PROCEDURES: In Experiment 1, three dogs were implanted with an antral strain gauge and bipolar electrodes for measurement of local tissue impedance. Impedance and strain gauge recordings were obtained simultaneously during antral contractions to correlate impedance changes with contractile events. In Experiment 2, seven dogs were implanted with two pairs of gastric electrodes for simultaneous recording of slow wave activity and impedance. The changes in the rate of slow waves and of antral contractions assessed by impedance during food intake were characterized. RESULTS: Variations in strain gauge amplitude were highly correlated with changes in antral impedance (R2: 0.70 to 0.82, p < 0.05). In Experiment 2, slow wave rate was significantly reduced after food intake and reached a nadir at satiation (5.0 +/- 0.3 vs. 3.8 +/- 0.5 events/min, p < 0.001). Likewise, the amplitude of antral contractions assessed by variations in impedance was significantly increased after food intake, peaking at satiation (5.3 +/- 1.4 vs. 12.2 +/- 4.3 Ohms, p < 0.01). DISCUSSION: Measurement of impedance is a reliable tool for assessing gastric contractility. Food ingestion significantly reduces slow wave rate and enhances antral contractions. Peak changes in these two variables occur at the time of satiation. Electrical measurements of both slow waves and impedance may be used to estimate gastric motility and satiation.

Enhancement of antral contractions and vagal afferent signaling with synchronized electrical stimulation.

Gastric filling activates vagal afferents involved in peripheral signaling to the central nervous system (CNS) for food intake. It is not known whether these afferents linearly encode increasing contractions of the antrum during antral distension (AD). The aim of this study was to investigate effects of AD and electrically enhanced antral contractions on responses of vagal afferents innervating the antrum. Single-fiber recordings were made from the vagal afferents in anesthetized male Long-Evans rats. Antral contractions were measured with a solid-state probe placed in the antrum. A nonexcitatory electrical stimulation (NES) inducing no smooth muscle contractions was applied during the ascending phase of antral contractions to enhance subsequent antral contractions. Fifty-six fibers identified during AD (1 ml for 30 s) were studied through different types of mechanical stimuli. Under normal conditions, one group of fibers exhibited rhythmic firing in phase with antral contractions. Another group of fibers had nonrhythmic spontaneous firing. Responses of 15 fibers were tested with NES during multiple-step distension (MSD). NES produced a mean increase in antral contraction amplitude (177.1 +/- 35.3%) and vagal afferent firing (21.6 +/- 2.6%). Results show that both passive distension and enhanced antral contractions activate distension-sensitive vagal afferents. Responses of these fibers increase linearly to enhanced antral contraction induced by NES or MSD up to a distending volume of 0.6 ml. However, responses reached a plateau at a distending volume >0.8 ml. We concluded that enhanced contraction of the antrum can activate vagal afferents signaling to the CNS.