The neurometabolic axis: A novel therapeutic target in heart failure.

Abnormal cardiac metabolism or cardiac metabolic remodeling is reported before the onset of heart failure with reduced ejection fraction (HFrEF) and is known to trigger and maintain the mechanical dysfunction and electrical, and structural abnormalities of the ventricle. A dysregulated cardiac autonomic tone characterized by sympathetic overdrive with blunted parasympathetic activation is another pathophysiological hallmark of HF. Emerging evidence suggests a link between autonomic nervous system activity and cardiac metabolism. Chronic ß-adrenergic activation promotes maladaptive metabolic remodeling whereas cholinergic activation attenuates the metabolic aberrations through favorable modulation of key metabolic regulatory molecules. Restoration of sympathovagal balance by neuromodulation strategies is emerging as a novel nonpharmacological treatment strategy in HF. The current review attempts to evaluate the 'neuro-metabolic axis' in HFrEF and whether neuromodulation can mitigate the adverse metabolic remodeling in HFrEF.

Atrial fibrillation in obstructive sleep apnea: Neural mechanisms and emerging therapies.

Obstructive sleep apnea (OSA) has been reproducibly identified as a risk factor for initiation and progression of atrial fibrillation (AF) and reduces the efficacy of antiarrhythmic drugs, electrical cardioversion, and catheter ablation in AF. It is still controversial whether continuous positive airway pressure ventilation (CPAP) could improve the successful rate of AF treatment in OSA patients. Besides, CPAP has shown relative low compliance in patients with OSA. Therefore, novel optional therapies might be needed to improve the control of AF associated with OSA. A growing body of evidence suggests that autonomic activation contributes to the pathogenesis of AF in OSA. Acute apneic episodes result in sympathovagal co-activation, shortening atrial refractoriness and promoting the initiation of AF. Chronic OSA-induced sympathetic activation plays a crucial role in atrial autonomic, structural, and electrical remodeling, thus providing substrates for AF maintenance and recurrence. Therefore, the autonomic nervous system may be a promising therapeutic target for OSA and AF. Autonomic modulation as a treatment for OSA-associated AF has been well established in several preclinical studies. Further clinical studies are needed to provide a more precise definition of the role of autonomic modulation in the treatment of AF in OSA.

Insulin Treatment Reduces Susceptibility to Atrial Fibrillation in Type 1 Diabetic Mice.

Diabetes has been identified as an independent risk factor for atrial fibrillation (AF), the most common chronic cardiac arrhythmia. Whether or not glucose and insulin disturbances observed during diabetes enhance arrhythmogenicity of the atria, potentially leading to AF, is not well-known. We hypothesized that insulin deficiency and impaired glucose transport provide a metabolic substrate for the development and maintenance of AF during diabetes. Transesophageal atrial pacing was used to induce AF in healthy, streptozotocin-induced insulin-deficient type 1 diabetic, and insulin-treated diabetic mice. Translocation of insulin-sensitive glucose transporters (GLUTs) to the atrial cell surface was measured using a biotinylated photolabeling assay in the perfused heart. Fibrosis and glycogen accumulation in the atrium were measured using histological analysis. Diabetic mice displayed mild hyperglycemia, increased duration and frequency of AF episodes vs. age-matched controls (e.g., AF duration: 19.7 ± 6.8 s vs. 1.8 ± 1.1 s, respectively, p = 0.032), whereas insulin-treated diabetic animals did not. The translocation of insulin-sensitive GLUT-4 and -8 to the atrial cell surface was significantly downregulated in the diabetic mice (by 67 and 79%, respectively; p ≤ 0.001), and rescued by insulin treatment. We did not observe fibrosis or glycogen accumulation in the atria of diabetic mice. Therefore, these data suggest that insulin and glucose disturbances were sufficient to induce AF susceptibility during mild diabetes.

Intrapericardial administration of anti-arrhythmic medications in patients with electrical storm.

INTRODUCTION: Electrical storm (ES) is cardiac electrical instability characterized by recurrent episodes of ventricular tachyarrhythmias. ES is associated with increased mortality and morbidity, hence requires prompt intervention. Treatment of underlying etiology is of prime importance in termination of ES. Anti-arrhythmic medications serve as an adjunctive therapy in suppression of ES by reducing myocardial excitability. The anti-arrhythmic conventionally employed is amiodarone in combination with non-selective beta-blockers to reduce the adrenergic input to myocardium. However, anti-arrhythmics at increased concentrations can lead to adverse systemic effects including hemodynamic instability. HYPOTHESIS: We hypothesize 1. The use of intravenous or oral anti-arrhythmic therapy for patients in electrical storm is limited by their toxicities and blood pressure lowering effect. Corollary 1. Injection of anti-arrhythmic medications into the pericardial space, an extra-vascular structure encasing the heart, provides an option for use of higher concentration of anti-arrhythmic while limiting systemic absorption. Corollary 2. The pericardial space has direct communication to the epicardium, the outer most layer of cardiac muscle, spatial proximity may allow for effective therapeutic options in electrical storm. We present experimental and clinical evidence in support of these hypothesis.

TREAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation): A Randomized Clinical Trial.

OBJECTIVES: This study was a sham-controlled, double-blind, randomized clinical trial to examine the effect of chronic low level tragus stimulation (LLTS) in patients with paroxysmal AF. BACKGROUND: Low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve at the tragus (LLTS) acutely suppresses atrial fibrillation (AF) in humans, but the chronic effect remains unknown. METHODS: LLTS (20 Hz, 1 mA below the discomfort threshold) was delivered using an ear clip attached to the tragus (active arm) (n = 26) or the ear lobe (sham control arm) (n = 27) for 1 h daily over 6 months. AF burden over 2-week periods was assessed by noninvasive continuous electrocardiogram monitoring at baseline, 3 months, and 6 months. Five-minute electrocardiography and serum were obtained at each visit to measure heart rate variability and inflammatory cytokines, respectively. RESULTS: Baseline characteristics were balanced between the 2 groups. Adherence to the stimulation protocol (≤4 sessions lost per month) was 75% in the active arm and 83% in the control arm (p > 0.05). At 6 months, the median AF burden was 85% lower in the active arm compared with the control arm (ratio of medians: 0.15; 95% confidence interval: 0.03 to 0.65; p = 0.011). Tumor necrosis factor-alpha was significantly decreased by 23% in the active group relative to the control group (ratio of medians: 0.77; 95% confidence interval: 0.63 to 0.94; p = 0.0093). Frequency domain indices of heart rate variability were significantly altered with active versus control stimulation (p < 0.01). No device-related side effects were observed. CONCLUSIONS: Chronic, intermittent LLTS resulted in lower AF burden than did sham control stimulation, supporting its use to treat paroxysmal AF in selected patients. (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation [TREAT-AF]; NCT02548754).

Atrioventricular junctional ablation: The good, the bad, the better.

BACKGROUND: The management of patients with atrial fibrillation and an abnormally fast ventricular response has been through the use of pharmacologic agents. In those cases where rate control cannot be achieved pharmacologically, a standard approach has been atrioventricular (AV) junctional ablation and ventricular pacemaker implantation to achieve a stable ventricular rate. Long-term ventricular pacing has been shown to result in diminished ventricular function that can lead to heart failure. OBJECTIVE: To describe an experimental and clinical study demonstrating a modified form of AV junction ablation. METHODS: Ablation of the slow and fast AV nodal input does not produce AV block. Ablation of the connection between the two induces AV block, leaving the AV node and His bundle intact. RESULTS: Subsequently the escape heart rate is close to normal and responds well to exercise. CONCLUSION: In a clinical study with a 42 month follow-up, the modified procedure resulted in significantly reduced pacemaker dependence and mortality compared to the standard AV ablation procedure.

The role of low-level vagus nerve stimulation in cardiac therapy.

Introduction: Cardiovascular diseases are accompanied by autonomic nervous system (ANS) imbalance which is characterized by decreased vagal tone. Preclinical and clinical studies have revealed that increasing vagal activity via vagus nerve stimulation (VNS) could protect the heart. Based on these studies, VNS has emerged as a potential non-pharmaceutical treatment strategy. Although it's still difficult to find the optimal stimulus parameters, however, in arrhythmia model, it is reported that low-level VNS (LL-VNS) exacts paradoxical effects from the high-level VNS. Thus, the concept of LL-VNS is introduced. Areas covered: Animal and human studies have discussed the safety and efficacy of VNS and LL-VNS, and this review will discuss the research data in cardiovascular diseases, including atrial arrhythmia, ventricular arrhythmia, ischemia/reperfusion injury, heart failure, and hypertension. Expert opinion: In this regard, various clinical studies have been performed to verify the safety and efficacy of VNS. It is shown that VNS is well-tolerated and safe, but the results of its efficacy are conflicting, which may well block the translational process of VNS. The appearance of LL-VNS brings new idea and inspiration, suggesting an important role of subthreshold stimulation. A better understanding of the LL-VNS will contribute to translational research of VNS.

Replicate separation from dead dwarf cells of Stentor coeruleus.

INTRODUCTION: The present studies initially show the induction of dwarf forms from the disrupted cells of the large unicellular organism, Stentor coeruleus. The dwarf cells placed in a toxic solution showed evidence of cell death. Within minutes a morphological replicate of the cell separates and subsequently fades. METHODS: Dehydration of the commercially available Stentor media in deep well slides (n = 9) caused disruption of the large cells. Rehydration with sterile media allowed formation of mobile dwarf forms. The latter (n = 9) placed in a toxic solution lost mobility and showed evidence of cell death, i.e., apoptosis. Deep well slides (n = 9) containing sterile Stentor media were used as controls. RESULTS: In the slides following dehydration/ rehydration of the living Stentor media, 7of 9 showed mobile dwarf cells compared to 0 of 9 with the sterile media alone, p < 0.05). Within 8-12 min, the stationary dwarf cell progressively released a morphological replicate of the dead cell which contained entrapped bacteria. Subsequent fading of the replicate allowed dispersion of the bacteria. CONCLUSION: These findings provide evidence that cell death indicated by apopotosis (blebbing) is followed by a sequence consisting of the progressive separation of a replicate image which is initially visible then becoming a progressively non-visible, faded image.

Low-level transcutaneous vagus nerve stimulation attenuates cardiac remodelling in a rat model of heart failure with preserved ejection fraction.

NEW FINDINGS: What is the central question of this study? What is the effect of chronic intermittent low-level transcutaneous vagus nerve stimulation on cardiac inflammation, fibrosis and diastolic dysfunction in a rat model of heart failure with preserved ejection fraction? What is the main finding and its importance? In salt-sensitive rats fed with high salt diet, low-level transcutaneous vagus nerve stimulation significantly attenuated blood pressure elevation, ameliorated diastolic function, and attenuated left ventricular inflammation and fibrosis compared to the sham group. Further studies to examine the efficacy of this novel treatment in humans are warranted. ABSTRACT: Inflammation and fibrosis play a central role in the development of heart failure with preserved ejection fraction (HFpEF). We previously showed that low-level, transcutaneous stimulation of the vagus nerve at the tragus (LLTS) is anti-inflammatory. We investigated the effect of chronic intermittent LLTS on cardiac inflammation, fibrosis and diastolic dysfunction in a rat model of HFpEF. Dahl salt-sensitive (DS) rats were randomized in three groups: low salt (LS, 0.3% NaCl; n = 12; control group without stimulation) and high salt (HS, 4% NaCl) with either active (n = 18) or sham (n = 18) LLTS at 7 weeks of age. After 6 weeks of diet (baseline), sham or active LLTS (20 Hz, 2 mA, 0.2 ms) was implemented for 30 min daily for 4 weeks. Echocardiography was performed at baseline and 4 weeks after treatment (endpoint). At endpoint, left ventricle (LV) histology and gene expression were examined. After 6 weeks of diets, HS rats developed hypertension and LV hypertrophy compared to LS rats. At endpoint, LLTS significantly attenuated blood pressure elevation, prevented the deterioration of diastolic function and improved LV circumferential strain, compared to the HS sham group. LV inflammatory cell infiltration and fibrosis were attenuated in the HS active compared to the HS sham group. Pro-inflammatory and pro-fibrotic genes (tumour necrosis factor, osteopontin, interleukin (IL)-11, IL-18 and IL-23A) were differentially altered in the two groups. Chronic intermittent LLTS ameliorates diastolic dysfunction, and attenuates cardiac inflammation and fibrosis in a rat model of HFpEF, suggesting that LLTS may be used clinically as a novel non-invasive neuromodulation therapy in HFpEF.

Autonomic Neuromodulation Acutely Ameliorates Left Ventricular Strain in Humans.

Low-level transcutaneous vagus nerve stimulation at the tragus (LLTS) is anti-adrenergic. We aimed to evaluate the acute effects of LLTS on left ventricular (LV) function and autonomic tone. Patients with diastolic dysfunction and preserved LV ejection fraction were enrolled in a prospective, randomized, double-blind, 2 × 2 cross-over study. Patients received two separate, 1-h sessions, at least 1 day apart, of active LLTS (20 Hz, 1 mA below the discomfort threshold) and sham stimulation. Echocardiography was performed after LLTS or sham stimulation to assess cardiac function. A 5-min ECG was performed to assess heart rate variability (HRV). Twenty-four patients were enrolled. LV global longitudinal strain improved by 1.8 ± 0.9% during active LLTS compared to sham stimulation (p = 0.001). Relative to baseline, HRV frequency domain components (low frequency, high frequency, and their ratio) were favorably altered after LLTS compared to sham stimulation (all p < 0.05). We concluded that LLTS acutely ameliorates cardiac mechanics by modulating the autonomic tone. Trial registration: NCT02983448.

Subthreshold Stimulation for His Bundle Pacing.

One of the drawbacks of permanent His bundle pacing has been the relatively high pacing thresholds. The present experimental study was proposed to address this issue. In this article the authors present preliminary evidence that His bundle pacing can be achieved with subthreshold stimulation, thereby providing for increased battery life and consequently longer replacement intervals. Possible mechanisms underlying the paradoxical effects of subthreshold stimulation before and after the onset of complete atrioventricular block are also discussed.