Metabolic profiles identify circulating biomarkers associated with heart failure in young single ventricle patients.

BACKGROUND: Children and young adults with single ventricle (SV) heart disease frequently develop heart failure (HF) that is intractable and difficult to treat. Our understanding of the molecular and biochemical reasons underlying this is imperfect. Thus, there is an urgent need for biomarkers that predict outcome and provide a rational basis for treatment, and advance our understanding of the basis of HF. OBJECTIVE: We sought to determine if a metabolomic approach would provide biochemical signatures of HF in SV children and young adults. If significant, these analytes might serve as biomarkers to predict outcome and inform on the biological mechanism(s) of HF. METHODS: We applied a multi-platform metabolomics approach composed of mass spectrometry (MS) and nuclear magnetic resonance (NMR) which yielded 495 and 26 metabolite measurements respectively. The plasma samples came from a cross-sectional set of young SV subjects, ages 2-19 years with ten control (Con) subjects and 16 SV subjects. Of the SV subjects, nine were diagnosed as congestive HF (SVHF), and 7 were not in HF. Metabolomic data were correlated with clinical status to determine if there was a signature associated with HF. RESULTS: There were no differences in age, height, weight or sex between the 3 cohorts. However, statistical analysis of the metabolomic profiles using ANOVA revealed 44 metabolites with significant differences between cohorts including 41 profiled by MS and 3 by NMR. These metabolites included acylcarnitines, amino acids, and bile acids, which distinguished Con from all SV subjects. Furthermore, metabolite profiles could distinguish between SV and SVHF subjects. CONCLUSION: These are the first data to demonstrate a clear metabolomic signature associated with HF in children and young adults with SV. Larger studies are warranted to determine if these findings are predictive of progression to HF in time to provide intervention.

Successful continuous positive airway pressure treatment reduces skin sympathetic nerve activity in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with cardiovascular diseases and increased sympathetic tone. We previously demonstrated that patients with OSA have increased skin sympathetic nerve activity (SKNA). OBJECTIVE: The purpose of this study was to test the hypothesis that continuous positive airway pressure (CPAP) treatment reduces SKNA. METHODS: The electrocardiogram, SKNA, and polysomnographic recording were recorded simultaneously in 9 patients with OSA. After baseline recording, CPAP titration was performed and the pressure was adjusted gradually for the optimal treatment, defined by reducing the apnea-hypopnea index (AHI) to ≤5/h. Otherwise the treatment was considered suboptimal (AHI > 5/h). Fast Fourier transform analyses were performed to investigate the frequency spectrum of SKNA. RESULTS: There were very low frequency (VLF), low frequency (LF), and high frequency (HF) oscillations in SKNA. The HF oscillation matched the frequency of respiration. OSA episodes were more frequently associated with the VLF and LF than with the HF oscillations of SKNA. Compared with baseline, CPAP significantly decreased the arousal index and AHI and increased the minimal and mean oxyhemoglobin levels. Optimal treatment significantly increased the dominant frequency and reduced the heart rate, average SKNA (aSKNA), SKNA burst duration, and total burst area. The dominant frequency negatively correlated with aSKNA. CONCLUSION: VLF, LF, and HF oscillations are observed in human SKNA recordings. Among them, VLF and LF oscillations are associated with OSA while HF oscillations are associated with normal breathing. CPAP therapy reduces aSKNA and shifts the frequency of SKNA oscillation from VLF or LF to HF.

Skin sympathetic nerve activity as a biomarker of fitness.

BACKGROUND: Exercise stress testing is frequently used to expose cardiac arrhythmias. Aerobic exercise conditioning has been used as a nonpharmacologic antiarrhythmic intervention. OBJECTIVE: The purpose of this study was to test the hypothesis that noninvasively recorded skin sympathetic nerve activity (SKNA) is increased during exercise and that SKNA response varies according to fitness levels. METHODS: Oxygen consumption (VO2) and SKNA were recorded in 39 patients undergoing an incremental exercise test. Patients were grouped by 5 levels of fitness based on age, sex, and VO2max. RESULTS: With exercise, all patients had a significant increase in average SKNA (aSKNA) (1.58 ± 1.12 µV to 4.50 ± 3.06 µV, P = .000) and heart rate (HR) (87.40 ± 20.42 bpm to 154.13 ± 16.82 bpm, P = .000). A mixed linear model of aSKNA was used with fixed effects of fitness, exercise time, and recovery time, and random effects of subject level intercept and slopes for exercise time and recovery times. The poor fitness group had significantly higher aSKNA than the other groups (P = .0273). For all subjects studied, aSKNA increased by 5% per minute with progression of exercise and decreased by 15% per minute with progression of recovery. The fitness variable encodes information on both comorbidities and body mass index (BMI). Once fitness level is known, comorbidities and BMI are not significantly associated with aSKNA. In all groups, aSKNA positively correlated with HR (R2 = 0.47 ± 0.23) and VO2 (R2 = 0.68 ± 0.25). CONCLUSION: Fitness level determines the magnitude and time course of SKNA increase during exercise. SKNA may be a useful fitness biomarker in exercise stress testing.

Skin sympathetic nerve activity and ventricular rate control during atrial fibrillation.

BACKGROUND: The relationship between the ventricular rate (VR) during atrial fibrillation (AF) and skin sympathetic nerve activity (SKNA) remains unclear. OBJECTIVE: The purpose of this study was to test the hypothesis that SKNA bursts accelerate VR during AF. METHODS: We simultaneously recorded electrocardiogram and SKNA in 8 patients (median age 66.0 years [interquartile range {IQR} 59.0-77.0 years]; 4 men [50%]) with 30 paroxysmal AF episodes (all >10-minute long) and 12 patients (73.0 years [IQR 60.5-80.0 years]; 6 men [50%]) with persistent AF. The average amplitude of SKNA (aSKNA [µV]) during AF was analyzed in 1-minute windows and binned, showing 2 Gaussian distributions. We used the mean + 3SD of the first Gaussian distribution as the threshold that separates burst from baseline (nonburst) SKNA. All 1-minute aSKNA values above the threshold were detected, and the area between aSKNA and baseline of every 1 minute was calculated and added as burst area. RESULTS: VR was higher during SKNA bursts than during the nonburst period (103 beats/min [IQR 83-113 beats/min] vs 88 beats/min [IQR 76-101 beats/min], respectively; P = .003). In the highest quartile of the burst area during persistent AF, the scatterplot of maximal aSKNA and VR during each SKNA burst shows higher aSKNA and VR. The overall estimate of the correlation between maximal VR and aSKNA during bursts show a positive correlation in the highest quartile of the burst area (0.64; 95% confidence interval 0.54-0.74; P < .0001). CONCLUSION: SKNA bursts are associated with VR acceleration. These SKNA bursts may be new therapeutic targets for rate control during AF.

Skin sympathetic nerve activity in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased cardiac arrhythmia and sudden cardiac death. We recently developed a new method (neuECG) to noninvasively measure electrocardiogram and skin sympathetic nerve activity (SKNA). OBJECTIVE: The purpose of this study was to test the hypothesis that SKNA measured during sleep study is higher in patients with OSA than in those without OSA. METHODS: We prospectively recorded neuECG and polysomnography in 26 patients undergoing a sleep study. Sleep stages were scored into rapid eye movement (REM), and non-REM sleep stages 1 (N1), 2 (N2), and 3 (N3). Average voltage of skin sympathetic nerve activity (aSKNA) and SKNA burst area were calculated for quantification. Apnea/hypopnea index (AHI) >5 per hour was used to diagnose OSA. RESULTS: There was a positive correlation (r = 0.549; P = .018) between SKNA burst area and the arousal index in OSA but not in the control group. aSKNA during sleep was 0.61 ± 0.09 µV in OSA patients (n = 18) and 0.53 ± 0.04 µV in control patients (n = 8; P = .025). Burst area was 3.26 (1.90-4.47) µV·s/min in OSA patients and 1.31 (0.67-1.94) µV·s/min in control (P = .047). More apparent differences were found during N2, when the burst area in OSA (3.06 [1.46-5.52] µV·s/min) was much higher than that of the control (0.89 [0.79-1.65] µV·s/min; P = .03). CONCLUSION: OSA patients have higher SKNA activity than control patients, with the most pronounced differences observed during N2. Arousal at the end of apnea episodes is associated with large SKNA bursts. Overlaps of aSKNA and SKNA burst area between groups suggest that not all OSA patients have increased sympathetic tone.

Skin sympathetic nerve activity and the temporal clustering of cardiac arrhythmias.

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).

Effects of anesthetic and sedative agents on sympathetic nerve activity.

BACKGROUND: The effects of sedative and anesthetic agents on sympathetic nerve activity (SNA) are poorly understood. OBJECTIVE: The purpose of this study was to determine the effects of commonly used sedative and anesthetic agents on SNA in ambulatory dogs and humans. METHODS: 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. RESULTS: 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. CONCLUSION: Propofol, methohexital, dexmedetomidine, morphine, and hydromorphone suppressed, but midazolam had no significant effects on, SNA.