Objectives The study tested the hypothesis that augmentation of the left ventricular (LV) wall thickness with direct intramyocardial injections of alginate hydrogel implants (AHI) reduces LV cavity size, restores LV shape, and improves LV function in dogs with heart failure (HF).Background Progressive LV dysfunction, enlargement, and chamber sphericity are features of HF associated with increased mortality and morbidity.Methods Studies were performed in 14 dogs with HF produced by intracoronary microembolizations (LV ejection fraction [EF] <30%). Dogs were randomized to AHI treatment (n = 8) or to sham-operated control (n = 6). During an open-chest procedure, dogs received either intramyocardial injections of 0.25 to 0.35 ml of alginate hydrogel (Algisyl-LVR, LoneStar Heart, Inc., Laguna Hills, California) or saline. Seven injections were made similar to 1.0 to 1.5 cm apart (total volume 1.8 to 2.1 ml) along the circumference of the LV free wall halfway between the apex and base starting from the anteroseptal groove and ending at the posteroseptal groove. Hemodynamic and ventriculographic measurements were made before treatment (PRE) and repeated post-surgery for up to 17 weeks (POST).Results Compared to control, AHI significantly reduced LV end-diastolic and end-systolic volumes and improved LV sphericity. AHI treatment significantly increased EF (26 +/- 0.4% at PRE to 31 +/- 0.4% at POST; p < 0.05) compared to the decreased EF seen in control dogs (27 +/- 0.3% at PRE to 24 +/- 1.3% at POST; p < 0.05). AHI treatment was well tolerated and was not associated with increased LV diastolic stiffness.Conclusions In HF dogs, circumferential augmentation of LV wall thickness with AHI improves LV structure and function. The results support continued development of AHI for the treatment of patients with advanced HF. (c) 2013 by the American College of Cardiology Foundation

BackgroundVagus nerve stimulation (VNS) is a promising therapy for chronic heart failure with multiple mechanisms of action that have been demonstrated in animal models and a pilot study in humans. Ivabradine, a selective sinus node If channel inhibitor, has been recently demonstrated to be effective in heart failure via heart rate (HR) reduction. The purpose of this study was to determine whether VNS therapy initiated with Ivabradine therapy was safe.MethodsThe study was conducted in 3 healthy normal canines treated for 30 days with Ivabradine at 15 mg/kg twice daily. They underwent 24 hour ECG Holters at baseline and on the 30th day to assess average HR and to determine if there were any de-novo cardiac arrhythmias. On day 30, the VNS system was implanted and was initiated at maximal clinical parameters (VNS-I) for 30 minutes, and then increased (VNS-II). ECG was continuously recorded; transthoracic echo and aortic pressure were recorded at baseline, after VNS-I and after VNS-II.ResultsThe comparison of mean HR, aortic pressure (AoP), left ventricular ractional shortening (LV FS) is in the table below. Continuous ECG recordings did not demonstrate any ventricular or atrial arrhythmias. VNS reduced HR in a dose-dependent fashion (on top of the HR reduction by Ivabradine). VNS delivered with Ivabradine was not associated with any change in LV FS, aortic pressure nor any LV or RV wall motion abnormalities. The reduction in heart rate was consistent with previous findings in dogs with heart failure receiving VNS over 3 months.ConclusionsTabled 1Average HR (beats/min)Mean AoP (mmHg)LV FS (%)PRE/VNS-I/VNS-IIPRE/VNS-I/VNS-IIPRE/VNS-I/VNS-IIMean110/93/83100/99/9543/44/44SEM14/9/815/13/84/5/3PRE=after ivabradine, before VNS therapy; VNS-I= 6 mA, 2 stimulation pulses per heart beat and 25% duty cycle; VNS-II= 8 mA, 3 stimulation pulses per beat and 33% duty cycle Open table in a new tab BackgroundVagus nerve stimulation (VNS) is a promising therapy for chronic heart failure with multiple mechanisms of action that have been demonstrated in animal models and a pilot study in humans. Ivabradine, a selective sinus node If channel inhibitor, has been recently demonstrated to be effective in heart failure via heart rate (HR) reduction. The purpose of this study was to determine whether VNS therapy initiated with Ivabradine therapy was safe. Vagus nerve stimulation (VNS) is a promising therapy for chronic heart failure with multiple mechanisms of action that have been demonstrated in animal models and a pilot study in humans. Ivabradine, a selective sinus node If channel inhibitor, has been recently demonstrated to be effective in heart failure via heart rate (HR) reduction. The purpose of this study was to determine whether VNS therapy initiated with Ivabradine therapy was safe. MethodsThe study was conducted in 3 healthy normal canines treated for 30 days with Ivabradine at 15 mg/kg twice daily. They underwent 24 hour ECG Holters at baseline and on the 30th day to assess average HR and to determine if there were any de-novo cardiac arrhythmias. On day 30, the VNS system was implanted and was initiated at maximal clinical parameters (VNS-I) for 30 minutes, and then increased (VNS-II). ECG was continuously recorded; transthoracic echo and aortic pressure were recorded at baseline, after VNS-I and after VNS-II. The study was conducted in 3 healthy normal canines treated for 30 days with Ivabradine at 15 mg/kg twice daily. They underwent 24 hour ECG Holters at baseline and on the 30th day to assess average HR and to determine if there were any de-novo cardiac arrhythmias. On day 30, the VNS system was implanted and was initiated at maximal clinical parameters (VNS-I) for 30 minutes, and then increased (VNS-II). ECG was continuously recorded; transthoracic echo and aortic pressure were recorded at baseline, after VNS-I and after VNS-II. ResultsThe comparison of mean HR, aortic pressure (AoP), left ventricular ractional shortening (LV FS) is in the table below. Continuous ECG recordings did not demonstrate any ventricular or atrial arrhythmias. VNS reduced HR in a dose-dependent fashion (on top of the HR reduction by Ivabradine). VNS delivered with Ivabradine was not associated with any change in LV FS, aortic pressure nor any LV or RV wall motion abnormalities. The reduction in heart rate was consistent with previous findings in dogs with heart failure receiving VNS over 3 months. The comparison of mean HR, aortic pressure (AoP), left ventricular ractional shortening (LV FS) is in the table below. Continuous ECG recordings did not demonstrate any ventricular or atrial arrhythmias. VNS reduced HR in a dose-dependent fashion (on top of the HR reduction by Ivabradine). VNS delivered with Ivabradine was not associated with any change in LV FS, aortic pressure nor any LV or RV wall motion abnormalities. The reduction in heart rate was consistent with previous findings in dogs with heart failure receiving VNS over 3 months. ConclusionsTabled 1Average HR (beats/min)Mean AoP (mmHg)LV FS (%)PRE/VNS-I/VNS-IIPRE/VNS-I/VNS-IIPRE/VNS-I/VNS-IIMean110/93/83100/99/9543/44/44SEM14/9/815/13/84/5/3PRE=after ivabradine, before VNS therapy; VNS-I= 6 mA, 2 stimulation pulses per heart beat and 25% duty cycle; VNS-II= 8 mA, 3 stimulation pulses per beat and 33% duty cycle Open table in a new tab PRE=after ivabradine, before VNS therapy; VNS-I= 6 mA, 2 stimulation pulses per heart beat and 25% duty cycle; VNS-II= 8 mA, 3 stimulation pulses per beat and 33% duty cycle

Background: JNJ-39588146/human Stresscopin (STC) is a newly identified peptide member of the corticotropin-releasing factor (CRF) family that binds selectively and with high affinity to the CRF typ...

The effects of vagal stimulation (VS) on cardiac energy substrate metabolism are unknown. We tested the hypothesis that acute VS alters the balance between free fatty acid (FFA) and carbohydrate oxidation and opposes the metabolic effects of β-adrenergic stimulation. A clinical-type selective stimulator of the vagal efferent fibres was connected to the intact right vagus in chronically instrumented dogs. VS was set to reduce heart rate by 30 beats min(-1), and the confounding effects of bradycardia were then eliminated by pacing the heart at 165 beats min(-1). [(3)H]Oleate and [(14)C]glucose were infused to measure FFA and glucose oxidation. The heart was subjected to β-adrenergic stress by infusing dobutamine at 5, 10 and 15 μg kg(-1) min(-1) before and during VS. VS did not significantly affect baseline cardiac performance, haemodynamics or myocardial metabolism. However, at peak dobutamine stress, VS attenuated the increase in left ventricular pressure-diameter area from 235.9 ± 72.8 to 167.3 ± 55.8%, and in cardiac oxygen consumption from 173.9 ± 23.3 to 127.89 ± 6.2% (both P < 0.05), and thus mechanical efficiency was not enhanced. The increase in glucose oxidation fell from 289.3 ± 55.5 to 131.1 ± 20.9% (P < 0.05), while FFA oxidation was not increased by β-adrenergic stress and fell below baseline during VS only at the lowest dose of dobutamine. The functional and in part the metabolic changes were reversed by 0.1 mg kg(-1) atropine i.v. Our data show that acute right VS does not affect baseline cardiac metabolism, but attenuates myocardial oxygen consumption and glucose oxidation in response to adrenergic stress, thus functioning as a cardio-selective antagonist to β-adrenergic activation.

IntroductionThe co‐existence of renal insufficiency (RI) in patients with heart failure (HF) often referred to as “cardiorenal syndrome” (CRS), carries an extremely poor prognosis. Understanding the pathophysiology of CRS and development of new therapeutics that address this complex syndrome are hindered by lack of appropriate animal models.ObjectiveWe tested the hypothesis that a unilateral nephrectomy with sustained increase in contralateral renal vein pressure in dogs with established HF would lead to RI with a rise in serum creatinine (sCr) and blood urea nitrogen (BUN) and can serve as a model of CRS.MethodsSix dogs with coronary microembolization‐induced heart failure (LV ejection fraction, EF <30%) were studied. A right nephrectomy was performed in all dogs and the distal left renal vein was banded to increase proximal renal vein pressure from ~10 to ~35 mmHg. sCr and BUN were measured preoperatively, and at 1, 2, 3, 4, 7, and 8 weeks thereafter. A diuretic challenge (DC) was administered (furosemide 80 mg IV) to all dogs 3–4 weeks after surgery. sCr and BUN were measured before and 5 hours after DC.ResultsAll dogs developed RI as evidenced by a significant rise in sCr and BUN that persisted for 8 weeks (Table). DC increased sCr from 1.3±0.1 to 1.6±0.1 mg/dL (p<0.003) and BUN from 24±1.8 to 33±1.8 mg/dL (p<0.001).ConclusionsThe results describe a reproducible canine model of chronic HF and RI (model of CRS) that responds to DC in a manner consistent with the response of CRS patients to IV diuretics.

This study examined the effects of localized intramyocardial injections of hepatocyte growth factor (HGF) naked DNA plasmid on the progression of left ventricular (LV) dysfunction and remodeling in dogs with moderate heart failure (HF). Twenty-one dogs with intracoronary microembolization-induced HF [LV ejection fraction (EF) = 35-40%] were randomized into three treatment groups, namely, high-dose HGF plasmid (4.0 mg, n = 7), low-dose HGF plasmid (0.4 mg, n = 7), and sham-operated controls treated with normal saline (n = 7). A total of 10-15 injections of HGF plasmid or saline were made directly into the anterior wall of LV. LV EF and end-systolic volume (ESV) were measured before randomization (pretreatment) and at the end of 3 mo of follow-up (posttreatment). Treatment effect (Δ) was calculated as the change from pre- to posttreatment. Protein expression of sarcoplasmic reticulum (SR) Ca(2+)-cycling proteins was determined in LV tissue obtained from the sites of HGF injection and remote areas. Low-dose HGF attenuated the decline in EF (ΔEF: -3 ± 1 vs. -8 ± 1%, P < 0.05) and the increase in ESV (ΔESV: 6 ± 2 vs. 10 ± 1 ml, P < 0.05) seen in control sham-operated dogs, whereas high-dose HGF significantly increased EF (ΔEF: 4 ± 1 vs. -8 ± 1%, P < 0.05) and prevented the increase in ΔESV (ESV: -1 ± 1 vs. 10 ± 1 ml, P < 0.05) compared with control dogs. Treatment with high- and low-dose HGF improved the expression of the SR Ca(2+)-cycling proteins compared with controls. In conclusion, regional intramyocardial injections of HGF naked DNA plasmid improve regional and global LV function and prevent progressive LV remodeling.

Chronic heart failure (HF) is associated with autonomic dysregulation characterized by a sustained increase in sympathetic drive and by withdrawal of parasympathetic activity. Sympathetic overdrive and increased heart rate are predictors of poor long-term outcome in patients with HF. Considerable evidence exists that supports the use of pharmacologic agents that partially inhibit sympathetic activity as effective long-term therapy for patients with HF; the classic example is the wide use of selective and non-selective beta-adrenergic receptor blockers. In contrast, modulation of parasympathetic activation as potential therapy for HF has received only limited attention over the years given its complex cardiovascular effects. In this article, we review the results of recent experimental animal studies that provide support for the possible use of electrical Vagus nerve stimulation (VNS) as a long-term therapy for the treatment of chronic HF. In addition to exploring the effects of chronic VNS on left ventricular (LV) function, the review will also address the effects of VNS on potential modifiers of the HF state that include cytokine production and nitric oxide elaboration. Finally, we will briefly review other nerve stimulation approaches which is also currently under investigation as potential therapeutic modalities for treating chronic HF.

Background: Adenosine Regulating Agents (ARAs) are compounds that selectively increase local endogenous adenosine release during episodes of cellular stress in which ATP breakdown exceeds ATP synth...

Tabled 1Sham-ControlAHI-TreatmentPre3 HoursPre3 HoursES AWT (cm)0.86 ± 0.030.86 ± 0.030.80 ± 0.020.92 ± 0.02∗ES PWT (cm)0.86 ± 0.030.85 ± 0.030.80 ± 0.010.93 ± 0.01∗EDV (ml)66 ± 1.866 ± 1.769 ± 2.363 ± 2.4∗ESV (ml)48 ± 1.348 ± 1.250 ± 1.839 ± 1.3∗EF (%)27 ± 0.428 ± 0.528 ± 0.838 ± 1.2∗ESSI1.43 ± 0.031.43 ± 0.031.27 ± 0.081.45 ± 0.06∗ESPVR (mmHg/ml)1.92 ± 0.362.06 ± 0.341.73 ± 0.292.82 ± 0.53∗EDPVR (mmHg/ml)0.145 ± 0.0210.190 ± 0.0210.200 ± 0.0440.152 ± 0.021∗ = p < 0.05 vs. Pre Open table in a new tab AHI also increased the slope of the ESPVR and tended to decrease slope of the EDPVR. Conclusions: AHI can be performed safely and without adverse effects on LV diastolic function. Unlike other approaches, AHI elicits rapid improvements in LV function and geometry. ∗ = p < 0.05 vs. Pre AHI also increased the slope of the ESPVR and tended to decrease slope of the EDPVR. Conclusions: AHI can be performed safely and without adverse effects on LV diastolic function. Unlike other approaches, AHI elicits rapid improvements in LV function and geometry.

BACKGROUND Strong vagus nerve stimulation (VNS) is routinely used to induce and maintain atrial fibrillation (AF) in acute animal studies. Taken as a surrogate of increased vagal tone, such observations suggest an arrhythmogenic role of VNS in AF. In contrast, VNS has been demonstrated to have profound therapeutic effects in heart failure and other ailments.OBJECTIVE The purpose of this study was to examine the relationship between right cervical VNS and AF, especially the potential arrhythmogenic effects of therapeutic VNS.METHODS The relationship between VNS intensities and AF inducibility was studied in eight acute dogs at baseline and four different Levels of VNS, which were set to prolong spontaneous sinus cycle Length (SCL) by 20%, 40%, 60%, or 100%. The effect of mild VNS treatment on AF induction was further investigated in six chronically instrumented conscious dogs. These dogs were implanted with right cervical VNS stimulators and specialized atrial pacemakers. VNS intensity was titrated to slow the sinus rate by 10%.RESULTS In acute studies, it was found that mild to moderate VNS (i.e., producing <= 40% SCL prolongation) did not increase AF inducibility, while strong VNS (i.e., producing >= 60% SCL prolongation) did. In chronic studies, compared with controls, AF induction did not change during the 4-week VNS treatment.CONCLUSIONS AF inducibility by right cervical VNS is intensity dependent: strong VNS (producing >= 60% SCL prolongation) facilitates AF, while moderate VNS (producing <= 40% SCL prolongation) appears not to affect AF. The nonarrhythmogenic effect of therapeutic chronic VNS was further verified in conscious animals. We conclude that VNS with moderate intensities can be used to deliver therapeutic benefits without arrhythmogenic risk.