Complex Arrhythmia Syndrome in a Knock-In Mouse Model Carrier of the N98S Mutation.

Background: Calmodulin mutations are associated with arrhythmia syndromes in humans. Exome sequencing previously identified a de novo mutation in resulting in a p.N98S substitution in a patient with sinus bradycardia and stress-induced bidirectional ventricular ectopy.

Advancing Research on the Complex Interrelations Between Atrial Fibrillation and Heart Failure: A Report From a US National Heart, Lung, and Blood Institute Virtual Workshop.

The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF.

Left cardiac sympathetic denervation reduces skin sympathetic nerve activity in patients with long QT syndrome.

Background: Although left cardiac sympathetic denervation (LCSD) is an effective antiarrhythmic therapy for patients with long QT syndrome (LQTS), direct evidence of reduced sympathetic activity after LCSD in humans is limited.

Objective: The purpose of this study was to assess skin sympathetic nerve activity (SKNA) in patients with LQTS undergoing LCSD.

Methods: We prospectively enrolled 17 patients with LQTS who underwent LCSD between 2017 and 2019.

Cardiac resynchronization therapy modulates peripheral sympathetic activity.

Background: Heightened sympathetic nerve activity has been associated with poorer prognosis in patients with reduced left ventricular systolic function (ie, heart failure with reduced ejection fraction [HFrEF]).

Objective: The purpose of this study was to investigate the effects of cardiac resynchronization therapy (CRT) on sympathetic nerve activity, measured by average skin sympathetic nerve activity (aSKNA).

Methods: This prospective study enrolled 36 patients with HFrEF who received CRT.

Subcutaneous nerve stimulation reduces sympathetic nerve activity in ambulatory dogs with myocardial infarction.

Background: Subcutaneous nerve stimulation (ScNS) remodels the stellate ganglion and reduces stellate ganglion nerve activity (SGNA) in dogs. Acute myocardial infarction (MI) increases SGNA through nerve sprouting.

Objective: The purpose of this study was to test the hypothesis that ScNS remodels the stellate ganglion and reduces SGNA in ambulatory dogs with acute MI.

Characterization of skin sympathetic nerve activity in patients with cardiomyopathy and ventricular arrhythmia.

Background: Heightened sympathetic nerve activity is associated with occurrence of ventricular arrhythmia (VA).

Objective: To investigate the association of skin sympathetic nerve activity (SKNA) and VA occurrence.

Methods: We prospectively enrolled 65 patients with severe cardiomyopathy.

Renal Denervation Update From the International Sympathetic Nervous System Summit: JACC State-of-the-Art Review.

Three recent renal denervation studies in both drug-naïve and drug-treated hypertensive patients demonstrated a significant reduction of ambulatory blood pressure compared with respective sham control groups. Improved trial design, selection of relevant patient cohorts, and optimized interventional procedures have likely contributed to these positive findings. However, substantial variability in the blood pressure response to renal denervation can still be observed and remains a challenging and important problem.

Subcutaneous nerve stimulation for rate control in ambulatory dogs with persistent atrial fibrillation.

Background: Subcutaneous nerve stimulation (ScNS) damages the stellate ganglion and improves rhythm control of atrial fibrillation (AF) in ambulatory dogs.

Objective: The purpose of this study was to test the hypothesis that thoracic ScNS can improve rate control in persistent AF.

Methods: We created persistent AF in 13 dogs and randomly assigned them to ScNS (n = 6) and sham control (n = 7) groups.

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca-activated K channels.

Apamin-sensitive small-conductance Ca-activated K (SK) current ( I) is encoded by Ca-activated K channel subfamily N ( KCNN) genes. I importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that I inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WT) and variant KCNN channels, and determined if the 5-HT receptor antagonist ondansetron blocks I.

Ganglionated plexi as neuromodulation targets for atrial fibrillation.

The autonomic nervous system plays an important role in the genesis of atrial fibrillation and is one of the candidate targets for atrial fibrillation therapy. This review focuses on the role of the autonomic nervous system in atrial fibrillation development and discusses the results of the ganglionated plexi catheter and surgical ablation in preclinical and clinical studies. The heart is innervated by the extrinsic and intrinsic autonomic nervous systems.

Small-Conductance Calcium-Activated Potassium Current in Normal Rabbit Cardiac Purkinje Cells.

Background: Purkinje cells (PCs) are important in cardiac arrhythmogenesis. Whether small-conductance calcium-activated potassium (SK) channels are present in PCs remains unclear. We tested the hypotheses that subtype 2 SK (SK2) channel proteins and apamin-sensitive SK currents are abundantly present in PCs.

Role of Apamin-Sensitive Calcium-Activated Small-Conductance Potassium Currents on the Mechanisms of Ventricular Fibrillation in Pacing-Induced Failing Rabbit Hearts.

Background: Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small-conductance calcium-activated potassium currents () are heterogeneously upregulated in failing hearts. We hypothesized that influences the location and stability of rotors during VF.

Translational neurocardiology: preclinical models and cardioneural integrative aspects.

Neuronal elements distributed throughout the cardiac nervous system, from the level of the insular cortex to the intrinsic cardiac nervous system, are in constant communication with one another to ensure that cardiac output matches the dynamic process of regional blood flow demand. Neural elements in their various 'levels' become differentially recruited in the transduction of sensory inputs arising from the heart, major vessels, other visceral organs and somatic structures to optimize neuronal coordination of regional cardiac function. This White Paper will review the relevant aspects of the structural and functional organization for autonomic control of the heart in normal conditions, how these systems remodel/adapt during cardiac disease, and finally how such knowledge can be leveraged in the evolving realm of autonomic regulation therapy for cardiac therapeutics.

Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells.

Background: The melanin synthesis enzyme dopachrome tautomerase (Dct) regulates intracellular Ca(2+) in melanocytes. Homozygous Dct knockout (Dct(-/-)) adult mice are vulnerable to atrial arrhythmias (AA).

Objective: The purpose of this study was to determine whether apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) currents are upregulated in Dct(-/-) mice and contribute to AA.

Voltage-Induced Ca²⁺ Release in Postganglionic Sympathetic Neurons in Adult Mice.

Recent studies have provided evidence that depolarization in the absence of extracellular Ca2+ can trigger Ca2+ release from internal stores in a variety of neuron subtypes. Here we examine whether postganglionic sympathetic neurons are able to mobilize Ca2+ from intracellular stores in response to depolarization, independent of Ca2+ influx. We measured changes in cytosolic ΔF/F0 in individual fluo-4 -loaded sympathetic ganglion neurons in response to maintained K+ depolarization in the presence (2 mM) and absence of extracellular Ca2+ ([Ca2+]e).

Intermittent left cervical vagal nerve stimulation damages the stellate ganglia and reduces the ventricular rate during sustained atrial fibrillation in ambulatory dogs.

Background: The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear.

Objective: The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF.

Methods: We performed left cervical VNS in ambulatory dogs while recording the left SG nerve activity (SGNA) and vagal nerve activity.

Subcutaneous nerve activity is more accurate than heart rate variability in estimating cardiac sympathetic tone in ambulatory dogs with myocardial infarction.

Background: We recently reported that subcutaneous nerve activity (SCNA) can be used to estimate sympathetic tone.

Objective: The purpose of this study was to test the hypothesis that left thoracic SCNA is more accurate than heart rate variability (HRV) in estimating cardiac sympathetic tone in ambulatory dogs with myocardial infarction (MI).

Methods: We used an implanted radiotransmitter to study left stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and thoracic SCNA in 9 dogs at baseline and up to 8 weeks after MI.

SK channels and ventricular arrhythmias in heart failure.

Small-conductance Ca(2+)-activated K(+) (SK) currents are important in the repolarization of normal atrial (but not ventricular) cardiomyocytes. However, recent studies showed that the SK currents are upregulated in failing ventricular cardiomyocytes, along with increased SK channel protein expression and enhanced sensitivity to intracellular Ca(2+). The SK channel activation may be either anti-arrhythmic or pro-arrhythmic, depending on the underlying clinical situations.