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

BACKGROUND: We recently reported that subcutaneous nerve activity (SCNA) can be used to estimate sympathetic tone. OBJECTIVE: The purpose of this study was to test the hypothesis that left thoracic SCNA is more accurate than heart rate variability (HRV) in estimating cardiac sympathetic tone in ambulatory dogs with myocardial infarction (MI). METHODS: We used an implanted radiotransmitter to study left stellate ganglion nerve activity (SGNA), vagal nerve activity (VNA), and thoracic SCNA in 9 dogs at baseline and up to 8 weeks after MI. HRV was determined based on time-domain, frequency-domain, and nonlinear analyses. RESULTS: 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. CONCLUSION: SCNA is more accurate than HRV in estimating cardiac sympathetic tone in ambulatory dogs with MI

Effects of Stellate Ganglion Cryoablation on Subcutaneous Nerve Activity and Atrial Tachyarrhythmias in a Canine Model of Pacing-Induced Heart Failure

OBJECTIVES: This study aimed to test the hypothesis that subcutaneous nerve activity (SCNA) can adequately estimate the cardiac sympathetic tone and the effects of cryoablation of the stellate ganglion in dogs with pacing-induced heart failure (HF). BACKGROUND: Recording of SCNA is a new method to estimate sympathetic tone in dogs. HF is known to increase sympathetic tone and atrial arrhythmias. METHODS: Twelve dogs with pacing-induced HF were studied using implanted radiotransmitters to record the stellate ganglia nerve activity (SGNA), vagal nerve activity, and SCNA. Of these, 6 dogs (ablation group) underwent bilateral stellate ganglia cryoablation before the rapid ventricular pacing; the remaining 6 dogs (control group) had rapid ventricular pacing only. In both groups, SCNA was compared with SGNA and the occurrence of arrhythmias. RESULTS: SCNA invariably increased before the 360 identified atrial tachyarrhythmia episodes in the 6 control dogs before and after HF induction. SCNA and SGNA correlated in all dogs with an average correlation coefficient of 0.64 (95% confidence interval: 0.58 to 0.70). Cryoablation of bilateral stellate ganglia significantly reduced SCNA from 0.34 ± 0.033 μV to 0.25 ± 0.028 μV (p = 0.03) and eliminated all atrial tachyarrhythmias. CONCLUSIONS: SCNA can be used to estimate cardiac sympathetic tone in dogs with pacing-induced HF. Cryoablation of the stellate ganglia reduced SCNA and arrhythmia vulnerability

Periostin Activation of Integrin Receptors on Sensory Neurons Induces Allergic Itch

Chronic allergic itch is a common symptom affecting millions of people and animals, but its pathogenesis is not fully explained. Herein, we show that periostin, abundantly expressed in the skin of patients with atopic dermatitis (AD), induces itch in mice, dogs, and monkeys. We identify the integrin αVβ3 expressed on a subset of sensory neurons as the periostin receptor. Using pharmacological and genetic approaches, we inhibited the function of neuronal integrin αVβ3, which significantly reduces periostin-induced itch in mice. Furthermore, we show that the cytokine TSLP, the application of AD-causing MC903 (calcipotriol), and house dust mites all induce periostin secretion. Finally, we establish that the JAK/STAT pathway is a key regulator of periostin secretion in keratinocytes. Altogether, our results identify a TSLP-periostin reciprocal activation loop that links the skin to the spinal cord via peripheral sensory neurons, and we characterize the non-canonical functional role of an integrin in itch

Identification and validation of genes with expression patterns inverse to multiple metastasis suppressor genes in breast cancer cell lines

Metastasis suppressor genes (MSGs) have contributed to an understanding of regulatory pathways unique to the lethal metastatic process. When re-expressed in experimental models, MSGs block cancer spread to, and colonization of distant sites without affecting primary tumor formation. Genes have been identified with expression patterns inverse to a single MSG, and found to encode functional, druggable signaling pathways. We now hypothesize that common signaling pathways mediate the effects of multiple MSGs. By gene expression profiling of human MCF7 breast carcinoma cells expressing a scrambled siRNA, or siRNAs to each of 19 validated MSGs (NME1, BRMS1, CD82, CDH1, CDH2, CDH11, CASP8, MAP2K4, MAP2K6, MAP2K7, MAPK14, GSN, ARHGDIB, AKAP12, DRG1, CD44, PEBP1, RRM1, KISS1), we identified genes whose expression was significantly opposite to at least five MSGs. Five genes were selected for further analysis: PDE5A, UGT1A, IL11RA, DNM3 and OAS1. After stable downregulation of each candidate gene in the aggressive human breast cancer cell line MDA-MB-231T, in vitro motility was significantly inhibited. Two stable clones downregulating PDE5A (phosphodiesterase 5A), an enzyme involved in the regulation of cGMP-specific signaling, exhibited no difference in cell proliferation, but reduced motility by 47 and 66 % compared to the empty vector-expressing cells (p = 0.01 and p = 0.005). In an experimental metastasis assay, two shPDE5A-MDA-MB-231T clones produced 47-62 % fewer lung metastases than shRNA-scramble expressing cells (p = 0.045 and p = 0.009 respectively). This study demonstrates that previously unrecognized genes are inversely related to the expression of multiple MSGs, contribute to aspects of metastasis, and may stand as novel therapeutic targets

Short-Term Rationing of Combination Antiretroviral Therapy: Impact on Morbidity, Mortality, and Loss to Follow-Up in a Large HIV Treatment Program in Western Kenya

Background. There was a 6-month shortage of antiretrovirals (cART) in Kenya. Methods. We assessed morbidity, mortality, and loss to follow-up (LTFU) in this retrospective analysis of adults who were enrolled during the six-month period with restricted cART (cap) or the six months prior (pre-cap) and eligible for cART at enrollment by the pre-cap standard. Cox models were used to adjust for potential confounders. Results. 9009 adults were eligible for analysis: 4,714 pre-cap and 4,295 during the cap. Median number of days from enrollment to cART initiation was 42 pre-cap and 56 for the cap (P < 0.001). After adjustment, individuals in the cap were at higher risk of mortality (HR = 1.21; 95% CI : 1.06–1.39) and LTFU (HR = 1.12; 95% CI : 1.04–1.22). There was no difference between the groups in their risk of developing a new AIDS-defining illness (HR = 0.92 95% CI 0.82–1.03). Conclusions. Rationing of cART, even for a relatively short period of six months, led to clinically adverse outcomes

Genetic mutations in African patients with atrial fibrillation: Rationale and design of the Study of Genetics of Atrial Fibrillation in an African Population (SIGNAL)

BACKGROUND: There is an urgent need to understand genetic associations with atrial fibrillation in ethnically diverse populations. There are no such data from sub-Saharan Africa, despite the fact that atrial fibrillation is one of the fastest growing diseases. Moreover, patients with valvular heart disease are underrepresented in studies of the genetics of atrial fibrillation. METHODS: We designed a case-control study of patients with and without a history of atrial fibrillation in Kenya. Cases with atrial fibrillation included those with and without valvular heart disease. Patients underwent clinical phenotyping and will have laboratory analysis and genetic testing of >240 candidate genes associated with cardiovascular diseases. A 12-month follow-up assessment will determine the groups' morbidity and mortality. The primary analyses will describe genetic and phenotypic associations with atrial fibrillation. RESULTS: We recruited 298 participants: 72 (24%) with nonvalvular atrial fibrillation, 78 (26%) with valvular atrial fibrillation, and 148 (50%) controls without atrial fibrillation. The mean age of cases and controls were 53 and 48 years, respectively. Most (69%) participants were female. Controls more often had hypertension (45%) than did those with valvular atrial fibrillation (27%). Diabetes and current tobacco smoking were uncommon. A history of stroke was present in 25% of cases and in 5% of controls. CONCLUSION: This is the first study determining genetic associations in valvular and nonvalvular atrial fibrillation in sub-Saharan Africa with a control population. The results advance knowledge about atrial fibrillation and will enhance international efforts to decrease atrial fibrillation-related morbidity

Skin sympathetic nerve activity precedes the onset and termination of paroxysmal atrial tachycardia and fibrillation

Background Skin sympathetic nerve activity (SKNA) is useful for estimating sympathetic tone in humans. Objective 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. Methods 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). Results 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). Conclusion 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

Design and rationale of the high-sensitivity Troponin T Rules Out Acute Cardiac Insufficiency Trial

BACKGROUND: Acute heart failure (AHF) is a common presentation in the Emergency Department (ED), and most patients are admitted to the hospital. Identification of patients with AHF who have a low risk of adverse events and are suitable for discharge from the ED is difficult, and an objective tool would be useful. METHODS: The highly sensitive Troponin T Rules Out Acute Cardiac Insufficiency Trial (TACIT) will enroll ED patients being treated for AHF. Patients will undergo standard ED evaluation and treatment. High-sensitivity troponin T (hsTnT) will be drawn at the time of enrollment and 3 hours after the initial draw. The initial hsTnT draw will be no more than 3 hours after initiation of therapy for AHF (vasodilator, loop diuretic, noninvasive ventilation). Treating clinicians will be blinded to hsTnT results. We will assess whether hsTnT, as a single measurement or in series, can accurately predict patients at low risk of short-term adverse events. CONCLUSION: TACIT will explore the value of hsTnT measurements in isolation, or in combination with other markers of disease severity, for the identification of ED patients with AHF who are at low risk of short-term adverse events

Using skin sympathetic nerve activity to estimate stellate ganglion nerve activity in dogs

BACKGROUND: Stellate ganglion nerve activity (SGNA) is important in cardiac arrhythmogenesis. However, direct recording of SGNA requires access to the thoracic cavity. Skin of upper thorax is innervated by sympathetic nerve fibers originating from the stellate ganglia and is easily accessible. OBJECTIVE: The purpose of this study was to test the hypothesis that thoracic skin nerve activity (SKNA) can be used to estimate SGNA. METHODS: We recorded SGNA and SKNAs using surface electrocardiogram leads in 5 anesthetized and 4 ambulatory dogs. Apamin injected into the right stellate ganglion abruptly increased both right SGNA and SKNA in 5 anesthetized dogs. We integrated nerve activities and averaged heart rate in each 1-minure window over 10 minutes. We implanted a radiotransmitter to record left SGNA in 4 ambulatory dogs (2 normal, 1 with myocardial infarction, 1 with intermittent rapid atrial pacing). After 2 weeks of recovery, we simultaneously recorded the SKNA and left SGNA continuously for 30 minutes when the dogs were ambulatory. RESULTS: There was a positive correlation [average r = 0.877, 95% confidence interval (CI) 0.732-1.000, P <.05 for each dog] between integrated skin nerve activity (iSKNA) and SGNA (iSGNA) and between iSKNA and heart rate (average r = 0.837, 95% CI 0.752-0.923, P <.05). Similar to that found in the anesthetized dogs, there was a positive correlation (average r = 0.746, 95% CI 0.527-0.964, P <.05) between iSKNA and iSGNA and between iSKNA and heart rate (average r = 0.706, 95% CI 0.484-0.927, P <.05). CONCLUSION: SKNAs can be used to estimate SGNA in dogs