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The effects of sedative and anesthetic agents on sympathetic nerve activity (SNA) are poorly understood.The purpose of this study was to determine the effects of commonly used sedative and anesthetic agents on SNA in ambulatory dogs and humans.We implanted radiotransmitters in 6 dogs to record stellate ganglion nerve activity (SGNA), subcutaneous nerve activity (ScNA), and blood pressure (BP). After recovery, we injected dexmedetomidine (3 μg/kg), morphine (0.1 mg/kg), hydromorphone (0.05 mg/kg), and midazolam (0.1 mg/kg) on different days. We also studied 12 human patients (10 male; age 68.0 ± 9.1 years old) undergoing cardioversion for atrial fibrillation with propofol (0.77 ± 0.18 mg/kg) or methohexital (0.65 mg/kg) anesthesia. Skin sympathetic nerve activity (SKNA) and electrocardiogram were recorded during the study.SGNA and ScNA were significantly suppressed immediately after administration of dexmedetomidine (P = .000 and P = .000, respectively), morphine (P = .011 and P = .014, respectively), and hydromorphone (P = .000 and P = .012, respectively), along with decreased BP and heart rate (HR) (P.001 for each). Midazolam had no significant effect on SGNA and ScNA (P = .248 and P = .149, respectively) but increased HR (P = .015) and decreased BP (P = .004) in ambulatory dogs. In patients undergoing cardioversion, bolus propofol administration significantly suppressed SKNA (from 1.11 ± 0.25 μV to 0.77 ± 0.15 μV; P = .001), and the effects lasted for at least 10 minutes after the final cardioversion shock. Methohexital decreased chest SKNA from 1.59 ± 0.45 μV to 1.22 ± 0.58 μV (P = .000) and arm SKNA from 0.76 ± 0.43 μV to 0.55 ± 0.07 μV (P = .001). The effects lasted for at least 10 minutes after the cardioversion shock.Propofol, methohexital, dexmedetomidine, morphine, and hydromorphone suppressed, but midazolam had no significant effects on, SNA.

Background and Hypothesis Lifetime risks for atrial fibrillation (AF) are 1 in 4 for people 40 years of age and older. Rate and rhythm control are both important strategies in managing patients with AF. However, not all patients respond to beta blocker therapy. We hypothesize that sympathetic tone is important in rate control of AF, but the importance varied among patients. Experimental Design or Project Methods neuECG is a new noninvasive method to record skin sympathetic nerve activity (SKNA) and electrocardiogram. The present research recruited and recorded 2 paroxysmal and 3 persistent AF patients for 24 hours using neuECG. The average voltage of SKNA (aSKNA) and ventricular rate during AF was analyzed in one-min windows. Results The preliminary data reveal strong correlations (r=.783, r=.640, respectively, p

Sudden cardiac death (SCD) accounts for approximately 360,000 deaths annually in the United States, and is the cause of half of all cardiovascular deaths. In patients with severely depressed left ventricular ejection fraction (LVEF), implantable cardioverter-defibrillators (ICDs) have been shown to significantly reduce total mortality, but many factors beyond LVEF influence the relative benefit afforded by ICD implantation. In fact, among patients with prior myocardial infarction, approximately half of all SCDs occur in patients without severe LV dysfunction, and in analyses of large ICD trials, certain patient subgroups derive no benefit to ICD implantation despite having low LVEF, often due to competing non-arrhythmic mortality. Improved risk stratification tools to help select patients who are likely to derive the most benefit from ICD implantation are therefore needed. This manuscript will review studies evaluating use of ICDs in patients with mild LV systolic dysfunction and LVEF >35%, currently available ICD risk stratification models, and the rationale for designing a cohort study to prospectively validate use of an ICD risk stratification score.

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. Methods Optical mapping was used to study the membrane potential of the right atrium in Langendorff perfused Dct −/− (n = 9) and Dct +/− (n = 9) mice. Results Apamin prolonged action potential duration (APD) by 18.8 ms (95% confidence interval [CI] 13.4–24.1 ms) in Dct −/− mice and by 11.5 ms (95% CI 5.4–17.6 ms) in Dct +/− mice at a pacing cycle length of 150 ms ( P = .047). The pacing cycle length threshold to induce APD alternans was 48 ms (95% CI 34–62 ms) for Dct −/− mice and 21 ms (95% CI 12–29 ms) for Dct +/− mice ( P = .002) at baseline, and it was 35 ms (95% CI 21–49 ms) for Dct −/− mice and 22 ms (95% CI 11–32 ms) for Dct +/− mice ( P = .025) after apamin administration. Apamin prolonged post-burst pacing APD by 8.9 ms (95% CI 3.9–14.0 ms) in Dct −/− mice and by 1.5 ms (95% CI 0.7–2.3 ms) in Dct +/− mice ( P = .005). Immunoblot and quantitative polymerase chain reaction analyses showed that protein and transcripts levels of SK1 and SK3 were increased in the right atrium of Dct −/− mice. AA inducibility (89% vs 11%; P = .003) and duration (281 seconds vs 66 seconds; P = .008) were greater in Dct −/− mice than in Dct +/− mice at baseline, but not different (22% vs 11%; P = 1.00) after apamin administration. Five of 8 (63%) induced atrial fibrillation episodes in Dct −/− mice had focal drivers. Conclusion Apamin-sensitive SK current upregulation in Dct −/− mice plays an important role in the mechanism of AA.

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.

The autonomic nervous system regulates all aspects of normal cardiac function, and is recognized to play a critical role in the pathophysiology of many cardiovascular diseases. As such, the value of neuroscience-based cardiovascular therapeutics is increasingly evident. This White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology, pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.

Cardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC-FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. The patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. Channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in four of seven αMyHC-FKBP12 mice but in none of eight nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts compared with NTG hearts. Interestingly, the mean action potential duration at 50% but not 90% was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, average peak Na+ current ( INa) density was dramatically reduced and the INa inactivation curve was shifted by approximately +7 mV in αMyHC-FKBP12 atrial myocytes, whereas the activation and recovery curves were unaltered. The Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav1.2 protein levels and peak L-type Ca2+ current density and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces the atrial Nav1.5 expression level and mean peak INa, which is associated with increased peak L-type Ca2+ current and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitated the development of local conduction block and altered action potential duration and spontaneous AF. NEW & NOTEWORTHY This study addresses a long-standing riddle regarding the role of FK506-binding protein 12 in cardiac physiology. The work provides further evidence that FK506-binding protein 12 is a critical component for regulating voltage-gated sodium current and in so doing has an important role in arrhythmogenic physiology, such as atrial fibrillation.

The ventricular conduction system (VCS), composed of the His bundle, the left and right bundle branches, and the Purkinje fiber network, rapidly propagates electrical impulses through the ventricles to coordinate chamber contraction. An ECG depicts VCS-mediated ventricular depolarization as the QRS interval. Disorders of the VCS may manifest as arrhythmias, and are associated with increased risk of sudden cardiac death and overall mortality. The genetic and developmental mechanisms underlying VCS dysfunction are poorly understood. Genome-wide association studies have identified multiple single nucleotide polymorphisms (SNPs) associated with VCS arrhythmias. A majority of these SNPs occur outside of coding domains, within intergenic or intronic regions. We hypothesize that such pathogenic SNPs may impact VCS development and function by altering the expression of critical genes. Two intergenic SNPs associated with QRS prolongation occur near the bHLH cardiac transcription factor HAND1 . We have identified a left ventricle (LV) enhancer, located between these two SNPs, that is necessary and sufficient for LV cis -regulatory activity. Two evolutionarily conserved GATA transcription factor consensus-binding sites within this enhancer are bound by GATA4 and necessary for cis -regulatory activity. CRISPR-mediated deletion of this enhancer dramatically reduced Hand1 expression solely within the LV. Mice homozygous for this deleted enhancer displayed dysregulated LV gene expression, morphologically abnormal His bundles and left bundle branches, and a VCS phenotype consistent with right bundle branch block. Genome-wide association analyses of human patients with QRS prolongation revealed additional, linked SNPs, one of which overlaps with a critical GATA cis -regulatory element within the LV-specific Hand1 enhancer. This SNP disrupts GATA4 binding. Ongoing studies of mice that genetically mimic these minor SNP variants will assess reduced Hand1 expression and impaired VCS function. We conclude that a LV-specific Hand1 enhancer is necessary for VCS development and a SNP associated with QRS prolongation directly influences GATA4 binding to a critical cis -regulatory element within this enhancer.

BACKGROUND. Simultaneous noninvasively recorded skin sympathetic nerve activity (SKNA) and electrocardiogram (neuECG) can be used to estimate cardiac sympathetic tone. We tested the hypothesis that large and prolonged SKNA bursts are associated with temporal clustering arrhythmias. METHODS. We recorded neuECG in 10 patients (69 ± 10 years old) with atrial fibrillation (AF) episodes and in 6 patients (50 ± 13 years old) with ventricular tachycardia (VT) or fibrillation (VF) episodes. Clustering was defined by an arrhythmic episode followed within 1 minute by spontaneous recurrences of the same arrhythmia. The neuECG signals were bandpass filtered between 500–1000 Hz to display SKNA. RESULTS. There were 22 AF clusters, including 231 AF episodes from 6 patients, and 9 VT/VF clusters, including 99 VT/VF episodes from 3 patients. A total duration of SKNA bursts associated with AF was longer than that during sinus rhythm (78.9 min/hour [interquartile range (IQR) 17.5–201.3] vs. 16.3 min/hour [IQR 14.5–18.5], P = 0.022). The burst amplitude associated with AF in clustering patients was significantly higher than that in nonclustering patients (1.54 μV [IQR 1.35–1.89], n = 114, vs. 1.20 μV [IQR 1.05–1.42], n = 21, P < 0.001). The SKNA bursts associated with VT/VF clusters lasted 9.3 ± 3.1 minutes, with peaks that averaged 1.13 ± 0.38 μV as compared with 0.79 ± 0.11 μV at baseline (P = 0.041). CONCLUSION. Large and sustained sympathetic nerve activities are associated with the temporal clustering of AF and VT/VF. FUNDING. This study was supported in part by NIH grants R42DA043391 (THE), R56 HL71140, TR002208-01, R01 HL139829 (PSC), a Charles Fisch Cardiovascular Research Award endowed by Suzanne B. Knoebel of the Krannert Institute of Cardiology (TK and THE), a Medtronic-Zipes Endowment, and the Indiana University Health-Indiana University School of Medicine Strategic Research Initiative (PSC).

AIMS: Phospholamban (PLB) is the key regulator of the cardiac Ca(2+) pump (SERCA2a)-mediated sarcoplasmic reticulum Ca(2+) stores. We recently reported that PLB is highly concentrated in the nuclear envelope (NE) from where it can modulate perinuclear Ca(2+) handling of the cardiomyocytes (CMs). Since inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) mediates nuclear Ca(2+) release, we examined whether the nuclear pool of PLB regulates IP(3)-induced nuclear Ca(2+) handling. METHODS AND RESULTS: Fluo-4 based confocal Ca(2+) imaging was performed to measure Ca(2+) dynamics across both nucleus and cytosol in saponin-permeabilized CMs isolated from wild-type (WT) or PLB-knockout (PLB-KO) mice. At diastolic intracellular Ca(2+) ([Ca(2+)](i)= 100 nM), the Fab fragment of the monoclonal PLB antibody (anti-PLB Fab) facilitated the formation and increased the length of spontaneous Ca(2+) waves (SCWs) originating from the nuclear region in CMs from WT but not from PLB-KO mice. We next examined nuclear Ca(2+) activities at basal condition and after sequential addition of IP(3), anti-PLB Fab, and the IP(3)R inhibitor 2-aminoethoxydiphenyl borate (2-APB) at a series of [Ca(2+)](i). In WT mice, at 10 nM [Ca(2+)](i) where ryanodine receptor (RyR2) based spontaneous Ca(2+) sparks rarely occurred, IP(3) increased fluorescence amplitude (F/F(0)) of overall nuclear region to 1.19 ± 0.02. Subsequent addition of anti-PLB Fab significantly decreased F/F(0) to 1.09 ± 0.02. At 50 nM [Ca(2+)](i), anti-PLB Fab not only decreased the overall nuclear F/F(0) previously elevated by IP(3), but also increased the amplitude and duration of spark-like nuclear Ca(2+) release events. These nuclear Ca(2+) releases were blocked by 2-APB. At 100 nM [Ca(2+)](i), IP(3) induced short SCWs originating from nucleus. Anti-PLB Fab transformed those short waves into long SCWs with propagation from the nucleus into the cytosol. In contrast, neither nuclear nor cytosolic Ca(2+) dynamics was affected by anti-PLB Fab in CMs from PLB-KO mice in all these conditions. Furthermore, in WT CMs pretreated with RyR2 blocker tetracaine, IP(3) and anti-PLB Fab still increased the magnitude of nuclear Ca(2+) release but failed to regenerate SCWs. Finally, anti-PLB Fab increased low Ca(2+) affinity mag-fluo 4 fluorescence intensity in the lumen of NE of nuclei isolated from WT but not in PLB-KO mice. CONCLUSION: PLB regulates nuclear Ca(2+) handling. By increasing Ca(2+) uptake into lumen of the NE and perhaps other perinuclear membranes, the acute reversal of PLB inhibition decreases global Ca(2+) concentration at rest in the nucleoplasm, and increases Ca(2+) release into the nucleus, through mechanisms involving IP(3)R and RyR2 in the vicinity.

Background The apamin-sensitive small-conductance calcium-activated K (SK) current IKAS modulates automaticity of the sinus node. IKAS blockade by apamin causes sinus bradycardia. Objective The purpose of this study was to test the hypothesis that IKAS modulates ventricular automaticity. Methods We tested the effects of apamin (100 nM) on ventricular escape rhythms in Langendorff-perfused rabbit ventricles with atrioventricular block (protocol 1) and on recorded transmembrane action potential of pseudotendons of superfused right ventricular endocardial preparations (protocol 2). Results All preparations exhibited spontaneous ventricular escape rhythms. In protocol 1, apamin decreased the atrial rate from 186.2 ± 18.0 bpm to 163.8 ± 18.7 bpm (N = 6; P = .006) but accelerated the ventricular escape rate from 51.5 ± 10.7 bpm to 98.2 ± 25.4 bpm (P = .031). Three preparations exhibited bursts of nonsustained ventricular tachycardia and pauses, resulting in repeated burst termination pattern. In protocol 2, apamin increased the ventricular escape rate from 70.2 ± 13.1 bpm to 110.1 ± 2.2 bpm (P = .035). Spontaneous phase 4 depolarization was recorded from the pseudotendons in 6 of 10 preparations at baseline and in 3 in the presence of apamin. There were no changes of phase 4 slope (18.37 ± 3.55 mV/s vs 18.93 ± 3.26 mV/s, N=3; P = .231, ), but the threshold of phase 0 activation (mV) reduced from –67.97 ± 1.53 to –75.26 ± 0.28 (P = .034). Addition of JTV-519, a ryanodine receptor 2 stabilizer, in 5 preparations reduced escape rate back to baseline. Conclusion Contrary to its bradycardic effect in the sinus node, IKAS blockade by apamin accelerates ventricular automaticity and causes repeated nonsustained ventricular tachycardia in normal ventricles. ryanodine receptor 2 blockade reversed the apamin effects on ventricular automaticity.

Sympathetic nerve activity is an important trigger of cardiac arrhythmia. Our laboratory recently developed a new method for non-invasive recording of the skin sympathetic nerve activity (SKNA) using conventional electrocardiography (ECG) patch electrodes. Recent studies showed that SKNA can adequately estimate sympathetic tone in humans. In order to improve the analysis of SKNA, we developed automatic standard assessment system based on the concept of microneurography and applied to non-invasive SKNA recording via 4 steps of signal processing. Every parameters in procedures can be manually selected by users in order to meet requirements. After using these signal processing, the results obtained by this system show improved nerve burst morphology and trend. Intuitive nerve discharge pattern and occurrence frequency can be automatically generated. Verification of the method with the cold water pressor test data further established the reliability and usefulness of the system. This new method offered a convenient tool to evaluate SKNA for comprehensive and detailed application in neurocardiology. The analysis system may facilitate the study between SKNA and cardiac arrhythmia, thus advance the field of neurocardiology research.

Apamin-sensitive small-conductance Ca(2+)-activated K(+) (SK) current (I(KAS)) is encoded by Ca(2+)-activated K(+) channel subfamily N (KCNN) genes. I(KAS) importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that I(KAS) 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(3) receptor antagonist ondansetron blocks I(KAS). We searched 2,306,335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNE1 and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 variant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca(2+) sensitivity, increasing I(KAS) density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WT and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced I(KAS) inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F503L KCNN2 variant increases Ca(2+) sensitivity and I(KAS) density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent I(KAS) blocker. NEW & NOTEWORTHY We showed that ondansetron, a 5-HT(3) receptor antagonist, blocks small-conductance Ca(2+)-activated K(+) (SK) current. Ondansetron may be useful in controlling arrhythmias in which increased SK current is a likely contributor. However, its SK-blocking effects may also facilitate the development of drug-induced long QT syndrome.

Traditional processor design incorporates voltage and frequency guardbands to ensure correct execution of operations under worst-case conditions. As transistor density increases and manufacturing processes improve, increasingly costly guardbands are required to deal with the impacts of environmental variability. The use of timing speculation can relax the tight constraint for worst-case design by allowing occasional errors, which are detected and corrected later by an error resilience mechanism. However, a program's performance may suffer owing to timing errors. This paper analyzes program behaviors and proposes a loop transformation technique for timing speculative architectures. We observe relationships between program behaviors and timing errors through a simulator. From the analytical results, a loop transformation technique is developed to reduce timing errors. It is implemented and evaluated using LLVM compiler infrastructure. For the tested benchmark programs, the proposed loop transformation can reduce timing error counts by up to 37%.

Software reliability is critical to the operation of modern computer systems. This paper proposes a software-based, process-level programming model for tolerating transient faults, which are errors that temporarily occur in systems. The programming model is portable as its design is based on UNIX POSIX system calls. It contains two modes to accomplish transient-fault detection and correction. The tested benchmark programs are modified to conform to the proposed programming model. Preliminary experiments using the tested benchmark programs show that the proposed approach can monitor failure, detect errors, and recover from transient faults.

BACKGROUND: Apamin-sensitive small conductance calcium-activated K current (I(KAS)) is upregulated during ventricular pacing and masks short-term cardiac memory (CM). OBJECTIVE: To determine the role of I(KAS) in long-term CM. METHODS: CM was created with 3-5 weeks of ventricular pacing and defined by a flat or inverted T-wave off pacing. Epicardial optical mapping was performed in both paced and normal ventricles. Action potential duration (APD(80)) was determined during RA pacing. Ventricular stability was tested before and after I(KAS) blockade. Four paced hearts and 4 normal hearts were used for western blotting and histology. RESULTS: There were no significant differences in either the echocardiographic parameters or in fibrosis levels between groups. Apamin induced more APD(80) prolongation in CM than in normal ventricles (9.6% [8.8%-10.5%] vs 3.1% [1.9%-4.3%], p

Background— Hypokalemia increases the vulnerability to ventricular fibrillation. We hypothesize that the apamin-sensitive small-conductance calcium-activated potassium current ( I KAS ) is activated during hypokalemia and that I KAS blockade is proarrhythmic. Methods and Results— Optical mapping was performed in 23 Langendorff-perfused rabbit ventricles with atrioventricular block and either right or left ventricular pacing during normokalemia or hypokalemia. Apamin prolonged the action potential duration (APD) measured to 80% repolarization (APD 80 ) by 26 milliseconds (95% confidence interval [CI], 14–37) during normokalemia and by 54 milliseconds (95% CI, 40–68) during hypokalemia ( P =0.01) at a 1000-millisecond pacing cycle length. In hypokalemic ventricles, apamin increased the maximal slope of APD restitution, the pacing cycle length threshold of APD alternans, the pacing cycle length for wave-break induction, and the area of spatially discordant APD alternans. Apamin significantly facilitated the induction of sustained ventricular fibrillation (from 3 of 9 hearts to 9 of 9 hearts; P =0.009). Short-term cardiac memory was assessed by the slope of APD 80 versus activation time. The slope increased from 0.01 (95% CI, −0.09 to 0.12) at baseline to 0.34 (95% CI, 0.23–0.44) after apamin ( P P =0.045) during left ventricular pacing. Patch-clamp studies confirmed increased I KAS in isolated rabbit ventricular myocytes during hypokalemia ( P =0.038). Conclusions— Hypokalemia activates I KAS to shorten APD and maintain repolarization reserve at late activation sites during ventricular pacing. I KAS blockade prominently lengthens the APD at late activation sites and facilitates ventricular fibrillation induction.

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. While the SK channel is a new target of anti-arrhythmic therapy, drug safety is still one of the major concerns.

We recently reported that subcutaneous nerve activity (SCNA) can be used to estimate sympathetic tone.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).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. HRV was determined based on time-domain, frequency-domain, and nonlinear analyses.The correlation coefficients between integrated SGNA and SCNA averaged 0.74 (95% confidence interval [CI] 0.41-1.06) at baseline and 0.82 (95% CI, 0.63-1.01) after MI (P.05 for both). The absolute values of the correlation coefficients were significantly larger than that between SGNA and HRV analysis based on time-domain, frequency-domain, and nonlinear analyses, respectively, at baseline (P.05 for all) and after MI (P.05 for all). There was a clear increment of SGNA and SCNA at 2, 4, 6, and 8 weeks after MI, whereas HRV parameters showed no significant changes. Significant circadian variations were noted in SCNA, SGNA, and all HRV parameters at baseline and after MI, respectively. Atrial tachycardia (AT) episodes were invariably preceded by SCNA and SGNA, which were progressively increased from 120th, 90th, 60th, to 30th seconds before AT onset. No such changes of HRV parameters were observed before AT onset.SCNA is more accurate than HRV in estimating cardiac sympathetic tone in ambulatory dogs with MI.

Background— The transmural distribution of apamin-sensitive small conductance Ca 2+ -activated K + (SK) current ( I KAS ) in failing human ventricles remains unclear. Methods and Results— We optically mapped left ventricular wedge preparations from 12 failing native hearts and 2 rejected cardiac allografts explanted during transplant surgery. We determined transmural action potential duration (APD) before and after 100 nmol/L apamin administration in all wedges and after sequential administration of apamin, chromanol, and E4031 in 4 wedges. Apamin prolonged APD from 363 ms (95% confidence interval [CI], 341–385) to 409 (95% CI, 385–434; P P =0.001) in 12 native failing hearts at 1000 ms pacing cycle length (PCL). The percent APD prolongation is negatively correlated with baseline APD and positively correlated with PCL. Only 1 wedge had M-cell islands. The percentages of APD prolongation in the last 4 hearts at 2000 ms PCL after apamin, chromanol, and E4031 were 9.1% (95% CI, 3.9–14.2), 17.3% (95% CI, 3.1–31.5), and 35.9% (95% CI, 15.7–56.1), respectively. Immunohistochemical staining of subtype 2 of SK protein showed increased expression in intercalated discs of myocytes. Conclusions— SK current is important in the transmural repolarization in failing human ventricles. The magnitude of I KAS is positively correlated with the PCL, but negatively correlated with APD when PCL is fixed. There is abundant subtype 2 of SK protein in the intercalated discs of myocytes.

Objectives The potential for beneficial effects of adipose-derived stem cells (ASCs) on myocardial perfusion and left ventricular dysfunction in myocardial ischemia (MI) has not been tested following intravenous delivery. Methods Surviving pigs following induction of MI were randomly assigned to 1 of 3 different groups: the placebo group (n = 7), the single bolus group (SB) (n = 7, 15 × 107 ASCs), or the divided dose group (DD) (n = 7, 5 × 107 ASCs/day for three consecutive days). Myocardial perfusion defect area and coronary flow reserve (CFR) were compared during the 28-day follow-up. Also, serial changes in the absolute number of circulating CD4+T and CD8+T cells were measured. Results The increases in ejection fraction were significantly greater in both the SB and the DD groups compared to the placebo group (5.4 ± 0.9%, 3.7 ± 0.7%, and −0.4 ± 0.6%, respectively), and the decrease in the perfusion defect area was significantly greater in the SB group than the placebo group (−36.3 ± 1.8 and −11.5 ± 2.8). CFR increased to a greater degree in the SB and the DD groups than in the placebo group (0.9 ± 0.2, 0.8 ± 0.1, and 0.2 ± 0.2, respectively). The circulating number of CD8+T cells was significantly greater in the SB and DD groups than the placebo group at day 7 (3,687 ± 317/µL, 3,454 ± 787/µL, and 1,928 ± 457/µL, respectively). The numbers of small vessels were significantly greater in the SB and the DD groups than the placebo group in the peri-infarct area. Conclusions Both intravenous SB and DD delivery of ASCs are effective modalities for the treatment of MI in swine. Intravenous delivery of ASCs, with its immunomodulatory and angiogenic effects, is an attractive noninvasive approach for myocardial rescue. © 2014 Wiley Periodicals, Inc.

Background and Objectives Recent studies showed that, in addition to parasympathetic nerves, cervical vagal nerves contained significant sympathetic nerves. We hypothesized that cervical vagal nerve stimulation (VNS) may capture the sympathetic nerves within the vagal nerve and activate the stellate ganglion. Materials and Methods We recorded left stellate ganglion nerve activity (SGNA), left thoracic vagal nerve activity (VNA), and subcutaneous electrocardiogram in seven dogs during left cervical VNS with 30 seconds on-time and 30 seconds off time. We then compared the SGNA between VNS on and off times. Results Cervical VNS at moderate (0.75 mA) output induced large SGNA, elevated heart rate (HR), and reduced HR variability, suggesting sympathetic activation. Further increase of the VNS output to >1.5 mA increased SGNA but did not significantly increase the HR, suggesting simultaneous sympathetic and parasympathetic activation. The differences of integrated SGNA and integrated VNA between VNS on and off times (ΔSGNA) increased progressively from 5.2 mV-s {95% confidence interval (CI): 1.25-9.06, p=0.018, n=7} at 1.0 mA to 13.7 mV-s (CI: 5.97-21.43, p=0.005, n=7) at 1.5 mA. The difference in HR (ΔHR, bpm) between on and off times was 5.8 bpm (CI: 0.28-11.29, p=0.042, n=7) at 1.0 mA and 5.3 bpm (CI 1.92 to 12.61, p=0.122, n=7) at 1.5 mA. Conclusion Intermittent cervical VNS may selectively capture the sympathetic components of the vagal nerve and excite the stellate ganglion at moderate output. Increasing the output may result in simultaneously sympathetic and parasympathetic capture.

OpenMP provides an easy-to-learn and powerful programming environment for the development of parallel programs. We propose here an algorithm for the automatic correction of the OpenMP tasking model. Assuming a compiler or programmer has identified task regions in the source programs, the proposed algorithm will automatically generate correct task clauses and synchronization. The proposed algorithm is implemented here based on the ROSE compiler infrastructure; 14 benchmark programs are tested, each of which has had all clauses in the task directives removed for the evaluation. The results of this experimental evaluation show that the proposed technique can successfully generate correct clauses for the tested benchmark programs. The proposed technique can simplify the parallelizing of programs using the OpenMP tasking model, making parallel programming more effective and productive.

Background Purkinje cells ( PC s) are important in cardiac arrhythmogenesis. Whether small‐conductance calcium‐activated potassium ( SK ) channels are present in PC s remains unclear. We tested the hypotheses that subtype 2 SK ( SK 2) channel proteins and apamin‐sensitive SK currents are abundantly present in PC s. Methods and Results We studied 25 normal rabbit ventricles, including 13 patch‐clamp studies, 4 for Western blotting, and 8 for immunohistochemical staining. Transmembrane action potentials were recorded in current‐clamp mode using the perforated‐patch technique. For PC s, the apamin (100 nmol/L) significantly prolonged action potential duration measured to 80% repolarization by an average of 10.4 ms (95% CI , 0.11–20.72) (n=9, P =0.047). Voltage‐clamp study showed that apamin‐sensitive SK current density was significantly larger in PC s compared with ventricular myocytes at potentials ≥0 mV. Western blotting of SK 2 expression showed that the SK 2 protein expression in the midmyocardium was 58% ( P =0.028) and the epicardium was 50% ( P =0.018) of that in the pseudotendons. Immunostaining of SK 2 protein showed that PCs stained stronger than ventricular myocytes. Confocal microscope study showed SK 2 protein was distributed to the periphery of the PC s. Conclusions SK 2 proteins are more abundantly present in the PC s than in the ventricular myocytes of normal rabbit ventricles. Apamin‐sensitive SK current is important in ventricular repolarization of normal PC s.

Objectives This study was designed to test the hypothesis that low-level vagal nerve stimulation (VNS) reduces the ventricular rate (VR) during atrial fibrillation (AF) through the activation of the inferior vena cava (IVC)–inferior atrial ganglionated plexus nerve activity (IAGPNA). Background Increased IVC-IAGPNA can suppress atrioventricular node conduction and slow VR in canine models of AF. Methods Persistent AF was induced in 6 dogs and the IVC-IAGPNA, right vagal nerve activity, left vagal nerve activity, and an electrocardiogram were recorded. After persistent AF was documented, VNS was programed to 14 s “on” and 1.1 min “off.” After 1 week, the VNS was reprogramed to 3 min off and stimulation continued for another week. Neural remodeling of the stellate ganglion (SG) was assessed with tyrosine hydroxylase staining and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining. Results Average IVC-IAGPNA was increased during both VNS 1.1 min off (8.20 ± 2.25 μV [95% confidence interval (CI): 6.33 to 9.53 μV]; p = 0.002) and 3 min off (7.96 ± 2.03 μV [95% CI: 6.30 to 9.27 μV]; p = 0.001) versus baseline (7.14 ± 2.20 μV [95% CI: 5.35 to 8.52 μV]). VR was reduced during both VNS 1.1 min off (123.29 ± 6.29 beats/min [95% CI: 116.69 to 129.89 beats/min]; p = 0.001) and 3 min off (120.01 ± 4.93 beats/min [95% CI: 114.84 to 125.18 beats/min]; p = 0.001) compared to baseline (142.04 ± 7.93 bpm [95% CI: 133.72 to 150.37]). Abnormal regions were observed in the left SG, but not in the right SG. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling–positive neurons were found in 22.2 ± 17.2% [95% CI: 0.9% to 43.5%] of left SG cells and 12.8 ± 8.4% [95% CI: 2.4% to 23.2%] of right SG cells. Conclusions Chronic low-level VNS increases IVC-IAGPNA and damages bilateral stellate ganglia. Both mechanisms could contribute to the underlying mechanism of VR control during AF.

We recently reported a new method (neuECG) to simultaneously record electrocardiogram (ECG) and skin sympathetic nerve activity (SKNA) in humans [(1)][1]. There was a significant association between SKNA and paroxysmal atrial tachyarrhythmias [(2)][2]. While our preliminary study showed that

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. The intrinsic autonomic nervous system consists of multiple ganglionated plexi and axons, which innervate the neighboring atrial myocardium and control their electrophysiological properties. Abnormal autonomic innervation has been observed in an animal model of atrial fibrillation and in humans. Direct recordings of autonomic nerve activity in canine models showed that atrial tachyarrhythmia episodes were invariably preceded by intrinsic cardiac autonomic nerve activity, thus supporting the importance of intrinsic cardiac autonomic nerve activity as the triggers for atrial tachyarrhythmia. Targeting ganglionated plexi with catheter ablation improves the outcomes of paroxysmal atrial fibrillation ablation in addition to pulmonary vein antrum isolation. Ablation of ganglionated plexi alone without pulmonary vein isolation is also useful in controlling paroxysmal atrial fibrillation in some patients. However, surgical ganglionated plexi ablation in patients with a large left atrium, persistent atrial fibrillation, and/or a history of prior catheter ablation does not result in additional benefits. These different outcomes suggest that ganglionated plexi ablation is effective in managing patients with paroxysmal atrial fibrillation, but its effects in patients with persistent atrial fibrillation and advanced atrial diseases might be limited.

Background We recently reported that skin sympathetic nerve activity (SKNA) can be used to estimate sympathetic tone in humans. In animal models, vagal nerve stimulation (VNS) can damage the stellate ganglion, reduce stellate ganglion nerve activity, and suppress cardiac arrhythmia. Whether VNS can suppress sympathetic tone in humans remains unclear. Objective The purpose of this study was to test the hypothesis that VNS suppresses SKNA in patients with drug-resistant epilepsy. Methods ECG patch electrodes were used to continuously record SKNA in 26 patients with drug-resistant epilepsy who were admitted for video electroencephalographic monitoring. Among them, 6 (2 men, age 40 ± 11 years) were previously treated with VNS and 20 (7 men, age 37 ± 8 years) were not. The signals from ECG leads I and II were filtered to detect SKNA. Results VNS had an on-time of 30 seconds and off-time of 158 ± 72 seconds, with output of 1.92 ± 0.42 mA at 24.17 ± 2.01 Hz. Average SKNA during VNS off-time was 1.06 μV (95% confidence interval [CI] 0.93–1.18) in lead I and 1.13 μV (95% CI 0.99–1.27) in lead II, which was significantly lower than 1.38 μV (95% CI 1.01–1.75; P = .036) and 1.38 μV (95% CI 0.98–1.78; P = .035) in the control group, respectively. Heart rate was 65 bpm (95% CI 59–71) in the VNS group, which was significantly lower than 77 bpm (95% CI 71–83) in the control group. Conclusion Patients with VNS had significantly lower SKNA than those without VNS.

During the past three decades, catheter and surgical ablation of atrial fibrillation (AF) have evolved from investigational procedures to their current role as effective treatment options for patients with AF. Surgical ablation of AF, using either standard, minimally invasive, or hybrid techniques, is available in most major hospitals throughout the world. Catheter ablation of AF is even more widely available, and is now the most commonly performed catheter ablation procedure. In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the European Cardiac Arrhythmia Society (ECAS).1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons (STS) and the American College of Cardiology (ACC). This Consensus Statement on Catheter and Surgical AF Ablation was rewritten in 2012 to reflect the many advances in AF ablation that had occurred in the interim.2 The rate of advancement in the tools, techniques, and outcomes of AF ablation continue to increase as enormous research efforts are focused on the mechanisms, outcomes, and treatment of AF. For this reason, the HRS initiated an effort to rewrite and update this Consensus Statement. Reflecting both the worldwide importance of AF, as well as the worldwide performance of AF ablation, this document is the result of a joint partnership between the HRS, EHRA, ECAS, the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Society of Cardiac Stimulation and Electrophysiology (Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia [SOLAECE]). The purpose of this 2017 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a writing group, convened by these five international societies. The writing group is charged with defining the indications, techniques, and outcomes of AF ablation procedures. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation and the reporting of outcomes, including definitions relevant to this topic. The writing group is composed of 60 experts representing 11 organizations: HRS, EHRA, ECAS, APHRS, SOLAECE, STS, ACC, American Heart Association (AHA), Canadian Heart Rhythm Society (CHRS), Japanese Heart Rhythm Society (JHRS), and Brazilian Society of Cardiac Arrhythmias (Sociedade Brasileira de Arritmias Cardiacas [SOBRAC]). All the members of the writing group, as well as peer reviewers of the document, have provided disclosure statements for all relationships that might be perceived as real or potential conflicts of interest. All author and peer reviewer disclosure information is provided in Appendix A and Appendix B. In writing a consensus document, it is recognized that consensus does not mean that there was complete agreement among all the writing group members. Surveys of the entire writing group were used to identify areas of consensus concerning performance of AF ablation procedures and to develop recommendations concerning the indications for catheter and surgical AF ablation. These recommendations were systematically balloted by the 60 writing group members and were approved by a minimum of 80% of these members. The recommendations were also subject to a 1-month public comment period. Each partnering and collaborating organization then officially reviewed, commented on, edited, and endorsed the final document and recommendations. The grading system for indication of class of evidence level was adapted based on that used by the ACC and the AHA.3,4 It is important to state, however, that this document is not a guideline. The indications for catheter and surgical ablation of AF, as well as recommendations for procedure performance, are presented with a Class and Level of Evidence (LOE) to be consistent with what the reader is familiar with seeing in guideline statements. A Class I recommendation means that the benefits of the AF ablation procedure markedly exceed the risks, and that AF ablation should be performed; a Class IIa recommendation means that the benefits of an AF ablation procedure exceed the risks, and that it is reasonable to perform AF ablation; a Class IIb recommendation means that the benefit of AF ablation is greater or equal to the risks, and that AF ablation may be considered; and a Class III recommendation means that AF ablation is of no proven benefit and is not recommended. The writing group reviewed and ranked evidence supporting current recommendations with the weight of evidence ranked as Level A if the data were derived from high-quality evidence from more than one randomized clinical trial, meta-analyses of high-quality randomized clinical trials, or one or more randomized clinical trials corroborated by high-quality registry studies. The writing group ranked available evidence as Level B-R when there was moderate-quality evidence from one or more randomized clinical trials, or meta-analyses of moderate-quality randomized clinical trials. Level B-NR was used to denote moderate-quality evidence from one or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies. This designation was also used to denote moderate-quality evidence from meta-analyses of such studies. Evidence was ranked as Level C-LD when the primary source of the recommendation was randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analyses of such studies, or physiological or mechanistic studies of human subjects. Level C-EO was defined as expert opinion based on the clinical experience of the writing group. Despite a large number of authors, the participation of several societies and professional organizations, and the attempts of the group to reflect the current knowledge in the field adequately, this document is not intended as a guideline. Rather, the group would like to refer to the current guidelines on AF management for the purpose of guiding overall AF management strategies.5,6 This consensus document is specifically focused on catheter and surgical ablation of AF, and summarizes the opinion of the writing group members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are caring for patients who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF, and those involved in research in the field of AF ablation. This statement is not intended to recommend or promote catheter or surgical ablation of AF. Rather, the ultimate judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all the circumstances presented by that patient. The main objective of this document is to improve patient care by providing a foundation of knowledge for those involved with catheter ablation of AF. A second major objective is to provide recommendations for designing clinical trials and reporting outcomes of clinical trials of AF ablation. It is recognized that this field continues to evolve rapidly. As this document was being prepared, further clinical trials of catheter and surgical ablation of AF were under way.

This paper develops a SIMD-based software fault tolerance technique for ARM processors. The core technique employs instruction-level redundant execution to tolerate bit-flipping errors. The proposed approach is implemented in the LLVM compiler to generate reliable code automatically. For the tested benchmark programs, preliminary experiments show that the proposed approach can correctly generate fault-tolerant codes at costs of 4.7%–70.2% performance degradation on average compared with the original versions. The fault-tolerant versions of code are 1.44–2.54 times larger than the original versions.

The development of high throughput technologies such as next generation sequencing (NGS) has allowed for thousands of DNA loci to be interrogated simultaneously in a fast and economical method for the detection of clinically deleterious variants. Whenever a clinical diagnosis is known, a targeted NGS approach involving the use of disease-specific gene panels can be employed. This approach is often valuable as it allows for a more specific and clinically relevant interpretation of results. Here we describe the customization, validation, and utilization of a commercially available targeted enrichment platform for the scalability of clinical diagnostic cardiovascular genetic tests, including the design of the gene panels, the technical parameters for the quality assurance (QA) and quality control (QC), the customization of the bioinformatics pipeline, and the post-bioinformatics analysis procedures. Regions of poor base coverage were detected and targeted by Sanger sequencing as needed. All panels were successfully validated using genotype-known DNA samples either commercially available or from research subjects previously tested in outside clinical laboratories. In our experience utilizing several of the sub-panels in a clinical setting with 33 real-life cardiovascular patients we found that 20% of tests requested were reported to have at least one pathogenic or likely pathogenic variant that could explain the patient phenotype. For each of these patients, the positive results may aid the clinical team and the patients in best developing a disease management plan and in identifying relatives at risk.

Sympathetic tone is important in cardiac arrhythmogenesis; however, methods to estimate sympathetic tone are either to invasive or require proper sinus node function that may be abnormal in disease states. Because of the direct and extensive connections among various nerve structures, it is possible for the sympathetic nerves in the various structures to activate simultaneously. Therefore, we hypothesized that nerve activity can be recorded from the skin and it can be used to estimate the cardiac sympathetic tone. Preclinical studies in canines demonstrated that nerve activity is detectable using conventional ECG electrodes and can be used to estimate cardiac sympathetic tone. Subsequent clinical studies further supported this concept. In addition to studying the autonomic mechanisms of cardiac arrhythmia, these new methods may have broad application in studying both cardiac and non-cardiac diseases.

Skin sympathetic nerve activity (SKNA) is useful for estimating sympathetic tone in humans.The purpose of this study was to test the hypotheses that (1) increased SKNA is associated with the onset and termination of paroxysmal atrial tachycardia (AT) and atrial fibrillation (AF) and (2) sinoatrial node response to SKNA is reduced in patients with more frequent AT or AF episodes.SKNA and electrocardiogram were recorded in 11 patients (4 men and 7 women; average age 66 ± 10 years), including 3 patients with AT (11 ± 18 episodes per patient) and 8 patients with AF (24 ± 26 episodes per patient).The average SKNA (aSKNA) 10 seconds before AT onset was 1.07 ± 0.10 μV and 10 seconds after termination was 1.27 ± 0.10 μV; both were significantly (P = .032 and P.0001) higher than that during sinus rhythm (0.97 ± 0.09 μV). The aSKNA 10 seconds before AF onset was 1.34 ± 0.07 μV and 10 seconds after termination was 1.31 ± 0.07 μV; both were significantly (P .0001) higher than that during sinus rhythm (1.04 ± 0.07 μV). The aSKNA before onset (P.0001) and after termination (P = .0011) was higher in AF than in AT. The sinus rate correlated (P.0001) with aSKNA in each patient (average r = 0.74; 95% confidence interval 0.65-0.84). The r value in each patient negatively correlated with the number of AT and AF episodes (r = -0.6493; 95% confidence interval -0.8990 to -0.08073; P = .0306).Increased SKNA was observed both at the onset and termination of AT and AF. Patients with more frequent AT and AF episodes had a weak correlation between sinus rate and aSKNA, suggesting sinoatrial node remodeling by tachycardia.

Background— Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small-conductance calcium-activated potassium currents ( I KAS ) are heterogeneously upregulated in failing hearts. We hypothesized that I KAS influences the location and stability of rotors during VF. Methods and Results— Optical mapping was performed on 9 rabbit hearts with pacing-induced heart failure. The epicardial right ventricular and left ventricular surfaces were simultaneously mapped in a Langendorff preparation. At baseline and after apamin (100 nmol/L) infusion, the action potential duration (APD 80 ) was determined, and VF was induced. Areas with a >50% increase in the maximum action potential duration (ΔAPD) after apamin infusion were considered to have a high I KAS distribution. At baseline, the distribution density of phase singularities during VF in high I KAS distribution areas was higher than in other areas (0.0035±0.0011 versus 0.0014±0.0010 phase singularities/pixel; P =0.004). In addition, high dominant frequencies also colocalized to high I KAS distribution areas (26.0 versus 17.9 Hz; P =0.003). These correlations were eliminated during VF after apamin infusion, as the number of phase singularities (17.2 versus 11.0; P =0.009) and dominant frequencies (22.1 versus 16.2 Hz; P =0.022) were all significantly decreased. In addition, reentrant spiral waves became unstable after apamin infusion, and the duration of VF decreased. Conclusions— The I KAS current influences the mechanism of VF in failing hearts as phase singularities, high dominant frequencies, and reentrant spiral waves all correlated to areas of high I KAS . Apamin eliminated this relationship and reduced VF vulnerability.

Background Atrial fibrillation (AF) is a major contributor to the global cardiovascular disease burden. The clinical profile and outcomes of AF patients with valvular heart diseases in sub-Saharan Africa (SSA) have not been adequately described. We assessed clinical features and 12-month outcomes of patients with valvular AF (vAF) in comparison to AF patients without valvular heart disease (nvAF) in western Kenya. Methods We performed a cohort study with retrospective data gathering to characterize risk factors and prospective data collection to characterize their hospitalization, stroke and mortality rates. Results The AF patients included 77 with vAF and 69 with nvAF. The mean (SD) age of vAF and nvAF patients were 37.9(14.5) and 69.4(12.3) years, respectively. There were significant differences (p

During the past three decades, catheter and surgical ablation of atrial fibrillation (AF) have evolved from investigational procedures to their current role as effective treatment options for patients with AF. Surgical ablation of AF, using either standard, minimally invasive, or hybrid techniques, is available in most major hospitals throughout the world. Catheter ablation of AF is even more widely available, and is now the most commonly performed catheter ablation procedure. In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the European Cardiac Arrhythmia Society (ECAS).1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons (STS) and the American College of Cardiology (ACC). This Consensus Statement on Catheter and Surgical AF Ablation was rewritten in 2012 to reflect the many advances in AF ablation that had occurred in the interim.2 The rate of advancement in the tools, techniques, and outcomes of AF ablation continue to increase as enormous research efforts are focused on the mechanisms, outcomes, and treatment of AF. For this reason, the HRS initiated an effort to rewrite and update this Consensus Statement. Reflecting both the worldwide importance of AF, as well as the worldwide performance of AF ablation, this document is the result of a joint partnership between the HRS, EHRA, ECAS, the Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Society of Cardiac Stimulation and Electrophysiology (Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia [SOLAECE]). The purpose of this 2017 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a writing group, convened by these five international societies. The writing group is charged with defining the indications, techniques, and outcomes of AF ablation procedures. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation and the reporting of outcomes, including definitions relevant to this topic. The writing group is composed of 60 experts representing 11 organizations: HRS, EHRA, ECAS, APHRS, SOLAECE, STS, ACC, American Heart Association (AHA), Canadian Heart Rhythm Society (CHRS), Japanese Heart Rhythm Society (JHRS), and Brazilian Society of Cardiac Arrhythmias (Sociedade Brasileira de Arritmias Cardiacas [SOBRAC]). All the members of the writing group, as well as peer reviewers of the document, have provided disclosure statements for all relationships that might be perceived as real or potential conflicts of interest. All author and peer reviewer disclosure information is provided in Appendix A and Appendix B. In writing a consensus document, it is recognized that consensus does not mean that there was complete agreement among all the writing group members. Surveys of the entire writing group were used to identify areas of consensus concerning performance of AF ablation procedures and to develop recommendations concerning the indications for catheter and surgical AF ablation. These recommendations were systematically balloted by the 60 writing group members and were approved by a minimum of 80% of these members. The recommendations were also subject to a 1-month public comment period. Each partnering and collaborating organization then officially reviewed, commented on, edited, and endorsed the final document and recommendations. The grading system for indication of class of evidence level was adapted based on that used by the ACC and the AHA.3,4 It is important to state, however, that this document is not a guideline. The indications for catheter and surgical ablation of AF, as well as recommendations for procedure performance, are presented with a Class and Level of Evidence (LOE) to be consistent with what the reader is familiar with seeing in guideline statements. A Class I recommendation means that the benefits of the AF ablation procedure markedly exceed the risks, and that AF ablation should be performed; a Class IIa recommendation means that the benefits of an AF ablation procedure exceed the risks, and that it is reasonable to perform AF ablation; a Class IIb recommendation means that the benefit of AF ablation is greater or equal to the risks, and that AF ablation may be considered; and a Class III recommendation means that AF ablation is of no proven benefit and is not recommended. The writing group reviewed and ranked evidence supporting current recommendations with the weight of evidence ranked as Level A if the data were derived from high-quality evidence from more than one randomized clinical trial, meta-analyses of high-quality randomized clinical trials, or one or more randomized clinical trials corroborated by high-quality registry studies. The writing group ranked available evidence as Level B-R when there was moderate-quality evidence from one or more randomized clinical trials, or meta-analyses of moderate-quality randomized clinical trials. Level B-NR was used to denote moderate-quality evidence from one or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies. This designation was also used to denote moderate-quality evidence from meta-analyses of such studies. Evidence was ranked as Level C-LD when the primary source of the recommendation was randomized or nonrandomized observational or registry studies with limitations of design or execution, meta-analyses of such studies, or physiological or mechanistic studies of human subjects. Level C-EO was defined as expert opinion based on the clinical experience of the writing group. Despite a large number of authors, the participation of several societies and professional organizations, and the attempts of the group to reflect the current knowledge in the field adequately, this document is not intended as a guideline. Rather, the group would like to refer to the current guidelines on AF management for the purpose of guiding overall AF management strategies.5,6 This consensus document is specifically focused on catheter and surgical ablation of AF, and summarizes the opinion of the writing group members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are caring for patients who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF, and those involved in research in the field of AF ablation. This statement is not intended to recommend or promote catheter or surgical ablation of AF. Rather, the ultimate judgment regarding care of a particular patient must be made by the health care provider and the patient in light of all the circumstances presented by that patient. The main objective of this document is to improve patient care by providing a foundation of knowledge for those involved with catheter ablation of AF. A second major objective is to provide recommendations for designing clinical trials and reporting outcomes of clinical trials of AF ablation. It is recognized that this field continues to evolve rapidly. As this document was being prepared, further clinical trials of catheter and surgical ablation of AF were under way.

Introduction We tested the hypothesis that subcutaneous nerve activity (SCNA) of the thorax correlates with the stellate ganglion nerve activity (SGNA) and can be used to estimate the sympathetic tone.

Background Vagus nerve stimulation (VNS) therapy has been used for chronic heart failure and is believed to improve imbalance of autonomic control by increasing parasympathetic activity. Although it is known that there is neural communication between the VN and the cervical sympathetic trunk, there are few data regarding the quantity and/or distribution of the sympathetic components within the vagus nerve (VN). Objective To examine the sympathetic components within the human VN and correlate them with the presence of cardiac and neurologic diseases. Methods We performed immunohistochemistry on 31 human cervical and thoracic VNs (total 104 VNs) from autopsies and reviewed the patients' records. We correlated the quantity of sympathetic nerve fibers within the VNs with cardiovascular and neurologic disease states. Results All 104 VNs contain tyrosine hydroxylase (TH)–positive (sympathetic) nerve fibers; the mean TH-positive areas were 5.47% in the right cervical VN, 3.97% in the left cervical VN, 5.11% in the right thoracic VN, and 4.20% in the left thoracic VN. The distribution of TH-positive nerve fibers varied from case to case: central, peripheral, or scattered throughout nerve bundles. No statistically significant differences in nerve morphology were seen between diseases in which VNS is considered effective (depression and chronic heart failure) and other cardiovascular diseases or neurodegenerative disease. Conclusion Human VNs contain sympathetic nerve fibers. The sympathetic component within the VN could play a role in physiologic effects reported with VNS. The recognition of sympathetic nerve fibers in the VNs may lead to better understanding of the therapeutic mechanisms of VNS.