The autonomic nervous system and the origins of neurocardiology.

Following new concepts by Bichat in the early 19th century, of organic and animal life centered around the ganglionic nervous system, over 100 years of anatomic studies and physiologic experimentation eventually resulted in Gaskell's 1916 book entitled "The Involuntary Nervous System" and Langley's 1921 book entitled "The Autonomic Nervous System." Neurology and cardiology emerged as specialties of medicine in the early 20th century. Although neurology made several prominent discoveries in neurophysiology during the first half of the 20th century, cardiology developed coronary care units and cardiac catheterization in the 1960s. Programmed electrical stimulation of the heart and noninvasive ambulatory monitoring provided new methodologies to study clinical cardiac arrhythmias. Experimentally, direct cardiac nerve stimulation of sympathetic nerve endings, as well as parasympathetic control of the atrioventricular node, provided the background to new detailed autonomic studies of the heart. Neurocardiology, perhaps initially more directed towards our understanding of sudden cardiac death, ultimately embraced an even significantly more complex scheme of local circuit neurons and near-endless loops of interconnecting neurons in the heart. Intrathoracic extracardiac and intracardiac ganglia have been recharacterized, both anatomically and physiologically, laying the groundwork for potential new therapies of cardiac neuromodulation.

The reuse of cardiac pacemakers and defibrillators: A convoluted history in an era of global health.

Following the development of permanent transvenous cardiac pacing in the 1960s, the costs of pacemakers quickly led to their reuse in both developed countries and in low-and middle-income countries (LMIC). Legal, ethical, and industrial factors gradually resulted in the termination of reuse in developed countries. Without health care budgets to pay for costly pacemaker technologies, nongovernmental organizations (NGOs), and other groups have provided support to physicians and hospitals treating patients with heart block in LMICs. Multiple other academic and private groups have also assisted such patients in LMICs. Pacemaker companies have provided physicians and hospitals with new devices (that have an expired package date or through charitable donations). Greater care of preparing and cleaning refurbished devices have demonstrated overwhelmingly the safety and effectiveness of reused devices. More recently, cardiac resynchronization therapy and implantable cardioverter-defibrillators have also been reused in patients in LMICs. While the globalization of noncommunicable diseases continues, patients with rhythm disorders in LMICs can no longer be left behind. While patients in developed countries only receive new devices to treat rhythm disorders, the practice of reused cardiac implantable electronic devices will expand in LMICs, until equal access to device technologies be made available to all.

Prevalence of left atrial appendage thrombus detected by transoesophageal echocardiography before catheter ablation of atrial fibrillation in patients anticoagulated with non-vitamin K antagonist oral anticoagulants.

AIMS: There is ongoing controversy about the need for routine transoesophageal echocardiography (TOE) prior to atrial fibrillation (AF) ablation. Recently, the debate was reignited by the publication of a large series of patients showing a prevalence of left atrial appendage thrombus (LAAT) on TOE of 4.4%. We sought to assess the prevalence of LAAT on TOE before AF ablation at our institution. METHODS AND RESULTS: Consecutive patients scheduled for AF ablation at our institution between January 2009 and December 2016 were included. All patients were on oral anticoagulation for at least 4 weeks prior to TOE. Transoesophageal echocardiographies were performed 3-5 days prior to scheduled AF ablation. Data were collected utilizing a prospective database. In all, 668 patients and 943 AF ablation procedures were included. Mean age was 64 ± 11 years, 72% were male, average CHADS2 score was 1.0 ± 1.0, and 72% of the patients had paroxysmal AF. At the time of ablation, 496 (53%) were on non-vitamin K antagonist oral anticoagulants (NOACs) and 447 (47%) were on Warfarin. There were three cases with LAAT (3/943, 0.3%), all of whom had persistent AF and were on Warfarin. Two patients underwent surgical ablation and the third patient did not undergo ablation. CONCLUSION: In our experience, the prevalence of LAAT in patients on anticoagulation therapy undergoing TOE before catheter ablation of AF is 0.3%, which was much lower than recently reported. None of the patients with paroxysmal AF or on NOACs were found to have LAAT. Rather than routine use of TOE prior to AF ablation, a risk-based approach should be considered.

A prospective placebo controlled randomized study of caffeine in patients with supraventricular tachycardia undergoing electrophysiologic testing.

INTRODUCTION: Patients with cardiac arrhythmias are generally instructed to avoid caffeine intake. A comprehensive evaluation of the electrophysiological effects of caffeine on atrial and ventricular tissues in humans has not previously been performed. METHODS AND RESULTS: Eighty patients (31 men, mean age 49 ± 14 years) with symptomatic supraventricular tachycardia (SVT) undergoing an electrophysiologic study (EPS) prior to catheter ablation were randomized to receive oral caffeine or placebo. Caffeine at a dosage of 5 mg/kg (moderate intake) or placebo tablets were administered orally at a mean time of 57 ± 13 minutes prior to the EPS. The median (IQR) caffeine level in patients receiving caffeine was 7.4 µg/mL (4.7-8.7), as compared with 0.15 (0.00-0.61) in patients receiving placebo, P < 0.0001. Caffeine was associated with a significant increase in resting systolic and diastolic blood pressures as compared with placebo, while the resting heart rate was not significantly different between both groups. Caffeine was not associated with significant effects on the effective refractory period of the atrium or ventricle, as well as on AV node conduction. SVT was induced in all but 3 patients; there was no significant difference between groups receiving placebo or caffeine on SVT inducibility or the cycle length of induced tachycardias. CONCLUSIONS: Caffeine, at moderate intake, was associated with significant increases in systolic and diastolic blood pressures, but had no evidence of a significant effect on cardiac conduction and refractoriness. Furthermore, no effect of caffeine on SVT induction or more rapid rates of induced tachycardias was found.

Contact force mapping and voltage thresholds during high-frequency stimulation of human cardiac ganglionated plexuses†.

AIMS: The intrinsic cardiac nervous system consists of ganglionated plexuses (GPs) localized epicardially to specific regions of the left atrium (LA). The relation between voltage thresholds and endocardial contact force associated with autonomic effects during stimulation of GPs has not previously been evaluated. METHODS AND RESULTS: Sixteen patients with symptomatic atrial fibrillation (AF) underwent mapping of GPs prior to radiofrequency ablation of AF. Pre-acquired computed tomographic images were merged with 3D non-fluoroscopic electroanatomic mapping of the LA. Using high-frequency stimulation (HFS), the voltage thresholds of GPs was obtained while patients received conscious sedation. At each location, the contact force measurement from the catheter was correlated with the voltage applied during HFS at 5, 10, or 15 V to obtain an autonomic effect, usually associated with asystole, or marked bradycardia. There were 192 applications of HFS, resulting in GP identification in all patients (mean 3.4 per patient, range 1-5). During HFS, an autonomic response was significantly more likely to occur at 10 V as compared with 5 V (P < 0.008). There was no significant relation between the measured contact force and the likelihood of obtaining an autonomic response. When performing HFS at 15 V, a sudden overshoot with maximal values of contact force of up to 100 g was also observed. High-frequency stimulation was well tolerated, without associated adverse events. CONCLUSION: An autonomic response during HFS was significantly more likely to occur at 10 V as compared with 5 V. Although the GPs are epicardial structures, significant contact force was not required for their localization.

Prevalence of cardiac sarcoidosis in patients presenting with monomorphic ventricular tachycardia.

INTRODUCTION: Sarcoidosis is a granulomatous disease of unknown etiology, which involves the heart in 5-25% of cases. Although ventricular tachycardia (VT) has been reported as the first presentation of sarcoidosis, its prevalence has not previously been investigated. In this prospective study, we sought to systematically investigate the prevalence of cardiac sarcoidosis (CS) in patients presenting with monomorphic VT (MMVT) and no previous history of sarcoidosis. METHODS: Consecutive patients presenting with MMVT to a tertiary care center were screened for inclusion. Patients with idiopathic VT, VT secondary to coronary artery disease, or prior diagnosis of sarcoidosis were excluded. Included patients underwent F-18-fluorodeoxyglucose positron emission tomography (PET) scan. In subjects with PET scanning suggestive of active myocardial inflammation, histological diagnosis was confirmed through extracardiac or endomyocardial biopsy (EMB). RESULTS: A total of 182 patients presented to our institution with VT between February 2010 and September 2012 and 14 subjects met inclusion criteria. Within this group, six of 14 (42%) patients had abnormal PET scans suggesting active myocardial inflammation. Four of the six patients had tissue biopsies that were diagnostic of sarcoidosis; the remaining two patients had guided EMB indicating nonspecific myocarditis. Atrioventricular block was observed in three of four (75%) patients with CS and none in 10 of the others (P = 0.022). Three of the four patients had pulmonary sarcoidosis and one patient had isolated CS. All four patients were treated with corticosteroids. CONCLUSION: In this prospective study, four of 14 (28%) patients presenting with MMVT (without idiopathic VT, ischemic VT, or known sarcoidosis) had CS as the underlying etiology. Clinicians should consider screening for CS in patients with unexplained MMVT.

Paradigm of genetic mosaicism and lone atrial fibrillation: physiological characterization of a connexin 43-deletion mutant identified from atrial tissue.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia observed in otherwise healthy individuals. Most lone AF cases are nonfamilial, leading to the assumption that a primary genetic origin is unlikely. In this study, we provide data supporting a novel paradigm that atrial tissue-specific genetic defects may be associated with sporadic cases of lone AF. METHODS AND RESULTS: We sequenced the entire coding region of the connexin 43 (Cx43) gene (GJA1) from atrial tissue and lymphocytes of 10 unrelated subjects with nonfamilial, lone AF who had undergone surgical pulmonary vein isolation. In the atrial tissue of 1 patient, we identified a novel frameshift mutation caused by a single nucleotide deletion (c.932delC) that predicted 36 aberrant amino acids followed by a premature stop codon, leading to truncation of the C-terminal domain of Cx43. The mutation was absent from the lymphocyte DNA of the patient, indicating genetic mosaicism. Protein trafficking studies demonstrated intracellular retention of the mutant protein and a dominant-negative effect on gap junction formation of both wild-type Cx43 and Cx40. Electrophysiological studies revealed no electrical coupling of cells expressing the mutant protein alone and significant reductions in coupling when coexpressed with wild-type connexins. CONCLUSIONS: This study reports atrial tissue genetic mosaicism of a novel loss-of-function Cx43 mutation associated with lone AF. These findings implicate somatic genetic defects of Cx43 as a potential cause of AF and support the paradigm that sporadic, nonfamilial cases of lone AF may arise from genetic mosaicism that creates heterogeneous coupling patterns, predisposing the tissue to reentrant arrhythmias.

Psychological adjustment in ICD patients living with advisory fidelis leads.

UNLABELLED: Psychological Adjustment and Fidelis ICD Leads. INTRODUCTION: Implantable cardioverter defibrillators (ICD) advisory notices present treatment dilemmas for physicians and patients. On one side, the risk of device malfunction and the likely severity of clinical sequelae have to be estimated. This estimate has to be weighed against the risks of surgery to replace the advisory component. It is unclear whether there is important psychological morbidity associated with living with an ICD under advisory and whether this should be factored into decision making. The study had 2 objectives: (1) to examine whether there is adverse psychological adjustment when an ICD is under advisory, and (2) to assess the psychological sequel of advisory ICD component malfunction. METHODS: This study focused on the Sprint Fidelis advisory. All patients in our practice who still had an in service Medtronic Fidelis lead were included in the study. Three groups were compared: advisory group but no fracture (n = 249), advisory group with lead fracture (n = 24), and a control group (n = 143). For both objectives, we used a general anxiety and depression instrument and also device-specific measures of psychological well being. RESULTS AND CONCLUSIONS: First, there was no evidence of differences in the psychological functioning of patients at risk of ICD lead malfunction compared to a control group. Second, patients who had experienced an ICD lead fracture had adverse psychological morbidity compared to control patients, and this appeared, primarily, to be related to receiving inappropriate shock(s) at the time of the fracture.

In-hospital mortality in 13,263 survivors of out-of-hospital cardiac arrest in Canada.

BACKGROUND: There is a substantial mortality rate in patients admitted alive after out-of-hospital cardiac arrest. The primary objective of our study was to examine trends in in-hospital survival in out-of-hospital cardiac arrest survivors in Canada between 1994 and 2004. The secondary objective was to examine predictors of in-hospital survival in these patients. METHODS: Data on hospital admissions from April 1, 1994, to March 31, 2004, were obtained from the Health Person-oriented Information Database, maintained by Statistics Canada. We included all patients with a primary diagnosis of cardiac arrest who survived to hospital admission. We assessed survival to hospital discharge in all patients admitted alive. RESULTS: In Canada, 13,263 patients survived community arrest between 1994 and 2004. The annual incidence of hospital admission after out-of-hospital cardiac arrest decreased by 33%, from 5.37 per 100,000 in 1994 to 3.63 per 100,000 in 2004 (P < .0001 for trend). Subsequently, 5,045 patients (38.03%) survived to hospital discharge. The survival rate did not change during the duration of the study. Invasive coronary artery disease management was associated with a greatly increased chance of survival (odds ratio 21.98, 95% CI 17.62-27.42). Also male gender, heart failure, and acute myocardial ischemia were independent positive predictors of survival to hospital discharge; greater age and comorbidities were negative predictors of survival. Finally, there were significant interprovincial variations in survival rates. CONCLUSIONS: Our study, the largest of its kind, has 4 main findings. Firstly, between 1993 and 2004, there was a significant and steady decline in admission rates after community cardiac arrest. Second, there was no change in the in-hospital survival rates. Thirdly, invasive management of coronary artery disease was associated with a greatly improved chance of survival, and finally, there were important regional variations in survival rates.

Evaluation of non-synonymous NPPA single nucleotide polymorphisms in atrial fibrillation.

AIMS: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is an important cause of morbidity and mortality. A genetic mutation in the NPPA gene, which encodes the atrial natriuretic peptide, has been identified as the putative causative factor in a family with an autosomal dominant pattern of inheritance for AF. Two common single nucleotide polymorphisms (SNPs) in NPPA, rs5063 and rs5065, result in amino acid changes of the primary peptide and have been previously implicated in conditions associated with AF, including stroke and hypertension. Recently, the rs5063 SNP has been reported to confer an increased risk of AF development in a Chinese population. We sought to examine the associations of both rs5063 and rs5065 with AF in two separate North American cohorts of European ancestry. METHODS AND RESULTS: Patients with early-onset AF, along with healthy controls, were recruited at the University of Ottawa Heart Institute (UOHI) and the Massachusetts General Hospital (MGH). Study participants were genotyped for rs5063 and rs5065 using a combination of restriction fragment length polymorphism analysis and DNA microarrays. The study genotyped a total of 620 AF cases and 2446 healthy controls. The UOHI arm of the study identified an odds ratio (OR) of 0.72 [95% confidence interval (CI): 0.42-1.24] for rs5063, whereas an OR of 1.33 (95% CI: 0.80-2.21) was observed in the MGH arm. The combined OR approximated unity (OR 0.99; 95% CI: 0.54-1.80). Analysis of rs5065 revealed an OR of 1.12 (95% CI: 0.84-1.48) in UOHI, 1.08 (95% CI 0.80-1.45) in MGH, and 1.10 (95% CI 0.90-1.35) when combined. CONCLUSION: Common non-synonymous genetic variants within NPPA in these two large North American cohorts of European ancestry are not associated with the development of AF.

Predictors of fracture risk of a small caliber implantable cardioverter defibrillator lead.

INTRODUCTION: The Sprint Fidelis 6949 implantable cardioverter defibrillator (ICD; Medtronic Inc., Minneapolis, MN, USA) lead has a high rate of fracture. Identification of predictors of subsequent fracture is useful in decision making about lead replacement and for future lead design. We sought to determine if there are clinical, procedural, or radiological features associated with a greater risk of subsequent lead fracture. METHODS: Patients with Sprint Fidelis 6949 lead fractures (Fracture group) were identified from our institutional database. Each patient in the Fracture group was matched to two controls, immediately preceeding and succeeding Sprint Fidelis 6949 implant. Clinical and procedural characteristics were compared. Chest radiographs performed 2 weeks after ICD implant were reviewed by an observer blinded to outcomes. The following features were assessed: ICD tip location, lead slack, kinking of the lead body (> or =90 degrees ), and presence of lead "crimping" within the anchoring sleeve. RESULTS: Twenty-six patients with Sprint Fidelis 6949 lead fractures were identified and were matched to 52 control patients. On univariate analysis, a higher left ventricular ejection fraction (LVEF), prior ipsilateral device implant, history of prior ICD lead fracture, and noncephalic venous access were associated with risk of lead fracture. On multivariate analysis, a higher LVEF was the only independent predictor of lead fracture (P = 0.006). Radiological features were similar between the two groups. CONCLUSIONS: In this study, a higher LVEF was associated with a greater risk of lead fracture in patients with Sprint Fidelis 6949 ICD leads. Radiographic features did not predict subsequent risk of lead fracture in our population. (PACE 2010; 437-443).

Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing.

Genetic mutations of the cardiac sodium channel (SCN5A) specific only to the phenotype of atrial fibrillation have recently been described. However, data on the biophysical properties of SCN5A variants associated with atrial fibrillation are scarce. In a mother and son with lone atrial fibrillation, we identified a novel SCN5A coding variant, K1493R, which altered a highly conserved residue in the DIII-IV linker and was located six amino acids downstream from the fast inactivation motif of sodium channels. Biophysical studies of K1493R in tsA201 cells demonstrated a significant positive shift in voltage-dependence of inactivation and a large ramp current near resting membrane potential, indicating a gain-of-function. Enhanced cellular excitability was observed in transfected HL-1 atrial cardiomyocytes, including spontaneous action potential depolarizations and a lower threshold for action potential firing. These novel biophysical observations provide molecular evidence linking cellular "hyperexcitability" as a mechanism inducing vulnerability to this common arrhythmia.

No long-term psychological morbidity living with an implantable cardioverter defibrillator under advisory: the Medtronic Marquis experience.

AIMS: It is unclear whether there is important psychological morbidity associated with living with an implantable cardioverter defibrillator (ICD) under advisory and whether this should be factored into decision-making. METHODS AND RESULTS: Our study focused on patients living with advisory Medtronic Marquis ICDs. Patient adjustment to the ICD was evaluated using a validated device-specific metric of patient acceptance, the Florida Patient Acceptance Survey (FPAS). A comparison group of patients with other models of ICDs that were not under an advisory also completed the study measure. The questionnaire return rate was 86/122 (70.5%) in the advisory group and 94/134 (70.1%) in the non-advisory group. Only one patient in our clinic elected for generator change due to severe anxiety. There were no differences in demographic or clinical variables between the groups. There were no differences in the mean total FPAS score between the two patient groups (advisory patients 85.97 +/- 14.95 and 86.23 +/- 15.76 for non-advisory, P=0.340). Also there were no differences in any of the subscores. Correlates of poor device acceptance were younger age and a history of electrical storm. CONCLUSION: We found no evidence of increased long-term psychological morbidity in patients living with an ICD under advisory compared with patients with an ICD not under advisory. Our data suggest that patients and physicians should avoid hasty decisions about ICD replacement for psychological reasons.

Inappropriate implantable cardioverter defibrillator shocks in fractured Sprint Fidelis leads associated with 'appropriate' interrogation.

We present two patients with fractures within the pace-sense circuit of their Medtronic Sprint Fidelis leads who received inappropriate shocks from their Medtronic defibrillators during device interrogation. This was not simply a coincidence, but due to electromagnetic interference induced within the Sprint Fidelis lead by the device programmer during two-way communication with the defibrillator. Our subsequent investigations have uncovered at least two other similar incidents in Canada. We have also discovered that the Medtronic 'Auto-resume' feature may leave future patients uniquely vulnerable to such inappropriate shocks in the future.

Remote magnetic navigation-assisted catheter ablation enhances catheter stability and ablation success with lower catheter temperatures.

BACKGROUND: It has been suggested that remote magnetic navigation (RMN) may provide enhanced catheter stability and substrate contact to aid in ablation. To date, no study has examined this claim. Accordingly, we compared the characteristics of the successful ablation of atrioventricular reentry tachycardia (AVNRT) using RMN with a matched population ablated using a conventional (CON) manual approach. METHODS: Sixteen patients who underwent RMN-assisted ablation of typical AVNRT were matched with 16 patients who had a CON-AVNRT ablation. RESULTS: All patients had successful slow pathway modification without complication. The mean catheter temperature achieved with the successful ablation was significantly lower with RMN than with CON (42 +/- 7 degrees C vs 47 +/- 3 degrees C, P

Sex differences in the relationship between amiodarone use and the need for permanent pacing in patients with atrial fibrillation.

BACKGROUND: Amiodarone use was associated with an increased need for pacemaker insertion in a retrospective study of patients with atrial fibrillation (AF) and prior myocardial infarction. The aims of this study were to determine prospectively whether amiodarone increases the need for pacemakers in a general population of patients with AF and whether this effect is modified by sex. METHODS: The study included 1005 patients with new-onset AF who were enrolled in the Fibrillation Registry Assessing Costs, Therapies, Adverse events, and Lifestyle (FRACTAL). Multivariable Cox regression models, including time-dependent covariates accounting for medication exposure, were used to evaluate the risk of pacemaker insertion associated with amiodarone use. RESULTS: Amiodarone use was associated with an increased risk of pacemaker insertion (hazard ratio [HR], 2.01; 95% confidence interval [CI], 1.08-3.76) after adjustment for age, sex, atrial flutter, coronary artery disease, heart failure, and hypertension. The effect of amiodarone use was modified by sex, with a significant risk in women but not in men (HR, 4.69; 95% CI, 1.99-11.05 vs HR, 1.05; 95% CI, 0.42-2.58 [P = .02]). This interaction remained significant after adjustment for weight, body mass index, weight-adjusted amiodarone dose, and use of other antiarrhythmic or rate control drugs. CONCLUSION: The risk of bradyarrhythmia requiring pacemaker insertion associated with amiodarone use for AF is significantly greater in women than in men, independent of weight or body mass index.