Aims: To test the hypothesis that spinal cord stimulation (SCS) acutely improves heart rate variability (HRV) and baroreceptor sensitivity (BRS) in patients with heart failure (HF). Methods: SCS (15 minutes) was delivered in four different settings: 90% of maximal tolerated stimulation amplitude (MTA) targeting the T1-T4 spinal cord segments (SCS90T1-4), 60% of MTA (SCS60T1-4), 90% of MTA with cranial (SCS90CR) and caudal (SCS90CA) electrode configuration. HRV and BRS were recorded continuously and stimulation was compared to device off. Results: Fifteen HF patients were included. SCS90T1-4 did not change the standard deviation of intervals between normal beats (SDNN, p = 0.90), BRS (p = 0.55) or other HRV parameters. In patients with baseline SDNN <50 ms, SCS90T1-4 significantly increased SDNN (p = 0.004). Conclusions: Acute SCS at 60-90% of MTA targeting upper thoracic spinal cord segments does not improve autonomic balance or baroreceptor sensitivity in unselected patients with heart failure but may improve HRV in patients with low SDNN.

Several preclinical studies have shown that spinal cord stimulation (SCS) reduces sympathetic activation, reverses adverse cardiac remodelling, improves pump function, and suppresses ventricular arrhythmias in animal models of heart failure (HF) with reduced ejection fraction and suppresses ventricular arrhythmias in animal models of HF with reduced ejection fraction.1–4 However, the mechanism of SCS benefit in experimental HF remains poorly defined, and data on SCS in patients with HF is limited. Several biomarkers reflect pivotal aspects of HF pathophysiology and severity (e.g. neurohormonal activation, inflammation and cytokine triggering), and cardiac injury and stress. The effect of SCS on these biomarkers in patients with chronic HF remains largely unknown. Therefore, the objective of the present study was to test the hypothesis that SCS improves levels of neurohormones, inflammatory markers and cytokines and that this is paralleled by a reduction in biomarkers reflecting cardiac stress and injury.

Background Spinal cord stimulation (SCS) reduces sympathetic activity in animal models of heart failure with reduced ejection fraction (HF) but limited data exist of SCS in patients with HF. The aim of the present study was to test the primary hypothesis that SCS reduces cardiac sympathetic nerve activity in HF patients. Secondary hypotheses were that SCS improves left ventricular function and dimension, exercise capacity, and clinical variables relevant to HF. Methods HF patients with a SCS device previously participating in the DEFEAT‐HF trial were included in this crossover study with 6‐week intervention periods (SCS‐ON and SCS‐OFF). SCS (50 Hz, 210‐μs pulse duration, aiming at T2–T4 segments) was delivered for 12 hours daily. Indices of myocardial sympathetic neuronal function (heart‐to‐mediastinum ratio, HMR) and activity (washout rate, WR) were assessed using 123 I‐metaiodobenzylguanidine (MIBG) scintigraphy. Echocardiography, exercise testing, and clinical data collection were also performed. Results We included 13 patients (65.3 ± 8.0 years, nine males) and MIBG scintigraphy data were available in 10. HMR was not different comparing SCS‐ON (1.37 ± 0.16) and SCS‐OFF (1.41 ± 0.21, P = 0.46). WR was also unchanged comparing SCS‐ON (41.5 ± 5.3) and SCS‐OFF (39.1 ± 5.8, P = 0.30). Similarly, average New York Heart Association class (2.4 ± 0.5 vs 2.3 ± 0.6, P = 0.34), quality of life score (24 ± 16 vs 24 ± 16, P = 0.94), and left ventricular dimension and function as well as exercise capacity were all unchanged comparing SCS‐ON and SCS‐OFF. Conclusion In patients with HF, SCS (12 hours daily, targeting the T2–T4 segments of the spinal cord) does not appear to influence cardiac sympathetic neuronal activity or function as assessed by MIBG scintigraphy.

BACKGROUND:Glucagon-like peptide-1 (GLP-1) is a hormone predominately synthesized and secreted by intestinal L-cells. GLP-1 modulates multiple cellular functions and its receptor agonists are now used clinically for diabetic treatment. Interestingly, preclinical and clinical evidence suggests that GLP-1 agonists produce beneficial effects on dysfunctional hearts via acting on myocardial GLP-1 receptors. As the effects of GLP-1 on myocyte electrophysiology are largely unknown, this study was to assess if GLP-1 could affect the cardiac voltage-gated L-type Ca2+ current (I(Ca)).METHODS:The whole-cell patch clamp method was used to record I(Ca) and action potentials in enzymatically isolated cardiomyocytes from adult canine left ventricles.RESULTS:Extracellular perfusion of GLP-1 (7-36 amide) at 5 nM increased I(Ca) by 23 ± 8% (p < 0.05, n = 7). Simultaneous bath perfusion of 5 nM GLP-1 plus 100 nM Exendin (9-39), a GLP-1 receptor antagonist, was unable to block the GLP-1-induced increase in I(Ca); however, the increase in I(Ca) was abolished if Exendin (9-39) was pre-applied 5 min prior to GLP-1 administration. Intracellular dialysis with a protein kinase A inhibitor also blocked the GLP-1-enhanced I(Ca). In addition, GLP-1 at 5 nM prolonged the durations of the action potentials by 128 ± 36 ms (p < 0.01) and 199 ± 76 ms (p < 0.05) at 50% and 90% repolarization (n = 6), respectively.CONCLUSIONS:Our data demonstrate that GLP-1 enhances I(Ca) in canine cardiomyocytes. The enhancement of I(Ca) is likely via the cAMP-dependent protein kinase A mechanism and may contribute, at least partially, to the prolongation of the action potential duration.

Cardiomyocytes are excitable cells that have the ability to contract after excitation, therefore, each heartbeat is an event of electrical mechanical coupling Cardiac electrical activity at different levels can be measured through variable means and modified by different drugs or medical devices Understanding the basic mechanisms of cardiac excitation is essential not only to a physiologist, but also to a cardiologist, because cardiac arrhythmias are a major health Issue in our society and clinical practice Diagnosis and therapy of arrhythmias requires understanding the cause or origin of each arrhythmia and making decisions to control or eliminate the arrhythmia Advances in basic research enhance our understanding of normal cell, tissue, and organ function (physiology) and also disease processes (pathophysiology), and hopefully lead to better clinical diagnosis and improved clinical therapies, either directly or indirectly Cardiomyocytes are the main component of a heart Their electrical activity is fundamentally a bioprocess determined by the transmembrane potential a voltage difference between the intracellular and extracellular compartments During a normal cardiac cycle, mechanical contraction always follows electrical excitation This chapter provides a basic overview of membrane excitability of cardiomyocytes and other excitable cells (i e, neuronal and skeletal)

Glucagon‐like peptide‐1 (GLP‐1) is a hormone predominately synthesized and secreted by intestinal L cells. The biological effects of GLP‐1 are most likely via stimulation of GLP‐1 receptors. Animal studies have shown that GLP‐1 may protect the heart from ischemic damage and improve cardiac function in heart failure. However, the effects of GLP‐1 on myocyte electrophysiology have not been investigated. In this study we assessed the effects of GLP‐1 on cardiac action potentials. Extracellular application of GLP‐1 (7‐36) at 5 nM significantly prolonged the duration of action potentials in isolated canine ventricular myocytes. The duration at 50% repolarization was prolonged from 124 ± 24 ms for control to 252 ± 30 ms for GLP‐1 (n = 6, p < 0.01). Such prolongation accompanied with an increase in L‐type Ca2+ currents. Other parameters, such as amplitude, threshold, maximum upstroke velocity of action potentials, were not changed by GLP‐1. The effect of action potential prolongation was reversible after washout of GLP‐1. Lower concentrations (<0.05 nM) of GLP‐1 had no such effect. Adding GLP‐1 (7‐36) at 30 nM to a culture medium for 24 hours significantly increased the beating rate of cultured neonatal rat ventricular cells. Our data demonstrate that GLP‐1 prolongs cardiac action potential duration and increases beating rate of cardiomyocytes. These effects probably relate to GLP‐1‐induced increase in Ca2+ currents.

Purpose: Hyperpolarization-activated cyclic nucleotide-gated (HCN) genes have been successfully used as a strategy for recreating cardiac biological pacemakers in animal models. However, optimal dose of HCN and toxicity from HCN overexpression have not been investigated. Therefore, we assessed the effects of various titers of adenoviral human HCN4-GFP vector (Adv-hHCN4) on cardiomyocytes. Methods: Neonatal rat ventricular myocytes (NRVMs) were isolated, selected and cultured on microelectrode arrays to assess their automaticities. Morphology and apoptosis with and without HCN or Ca 2+ channel inhibitor were also assessed. Results: Beating rates significantly increased in NRVMs after hHCN4 infection (Fig. 1 ). For example, the rates were gradually increased to 235±11 beat/min on day 7 after hHCN4 infection with 1×10 5 PFU/array. In contrast, control cells showed low rates. NRVMs with ≥10 6 PFU/array Adv-hHCN4 reached faster rates early and subsequently stopped beating (Fig. 1 ). In addition, myocytes with ≥10 6 PFU/array Adv-hHCN4 underwent significant apoptosis (>50%) which potentially resulted from hHCN4 overexpression and was blocked by the HCN channel blocker Cs + (1 mM), but not by the Ca 2+ channel inhibitor nifedipine. In addition, myocytes infected with ≥10 6 PFU/array Adv-GFP maintained normal morphology and rate. Our data demonstrate that hHCN4 transfer significantly and dose-dependently increased beating rates of NRVMs. However, overexpression of HCN could cause apoptosis. Therefore, an optimal dose of HCN gene is important for reducing toxicity and creating stable and long-lasting biopacing activity in cardiomyocytes in vitro, and probably also in vivo. Figure 1. Effects of hHCN4 infection on automaticities of neonatal rat ventricular myocytes. Each data point represents an averaged beating rate (mean ± SE) from 8 to 10 arrays. Various titers (1×10 5 to 1×10 7 PFU/500,000 cells per array) of Adv-Hhcn4 (expect control) were added to the arrays after measurements on day 0 (see the arrow)