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Chinda K.,Indiana University | Chinda K.,Chiang Mai University | Chinda K.,Naresuan University | Tsai W.-C.,Indiana University | And 19 more authors.
Heart Rhythm | Year: 2016

Background The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear. Objective The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF. Methods We performed left cervical VNS in ambulatory dogs while recording the left SG nerve activity (SGNA) and vagal nerve activity. Tyrosine hydroxylase (TH) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess neuronal cell death in the SG. Results We induced persistent AF by atrial pacing in 6 dogs, followed by intermittent VNS with short ON-time (14 seconds) and long OFF-time (66 seconds). The integrated SGNA and VR during AF were 4.84 mV·s (95% confidence interval [CI] 3.08-6.60 mV·s) and 142 beats/min (95% CI 116-168 beats/min), respectively. During AF, VNS reduced the integrated SGNA and VR, respectively, to 3.74 mV·s (95% CI 2.27-5.20 mV·s; P =.021) and 115 beats/min (95% CI 96-134 beats/min; P =.016) during 66-second OFF-time and to 4.07 mV·s (95% CI 2.42-5.72 mV·s; P =.037) and 114 beats/min (95% CI 83-146 beats/min; P =.039) during 3-minute OFF-time. VNS increased the frequencies of prolonged (>3 seconds) pauses during AF. TH staining showed large confluent areas of damage in the left SG, characterized by pyknotic nuclei, reduced TH staining, increased percentage of TH-negative ganglion cells, and positive TUNEL staining. Occasional TUNEL-positive ganglion cells were also observed in the right SG. Conclusion VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF. © 2016 Heart Rhythm Society. All rights reserved.


PubMed | Chang Gung University, Virginia Commonwealth University, Indiana University, National Chiao Tung University and 4 more.
Type: Journal Article | Journal: Heart rhythm | Year: 2016

The effects of intermittent open-loop vagal nerve stimulation (VNS) on the ventricular rate (VR) during atrial fibrillation (AF) remain unclear.The purpose of this study was to test the hypothesis that VNS damages the stellate ganglion (SG) and improves VR control during persistent AF.We performed left cervical VNS in ambulatory dogs while recording the left SG nerve activity (SGNA) and vagal nerve activity. Tyrosine hydroxylase (TH) staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to assess neuronal cell death in the SG.We induced persistent AF by atrial pacing in 6 dogs, followed by intermittent VNS with short ON-time (14 seconds) and long OFF-time (66 seconds). The integrated SGNA and VR during AF were 4.84 mVs (95% confidence interval [CI] 3.08-6.60 mVs) and 142 beats/min (95% CI 116-168 beats/min), respectively. During AF, VNS reduced the integrated SGNA and VR, respectively, to 3.74 mVs (95% CI 2.27-5.20 mVs; P = .021) and 115 beats/min (95% CI 96-134 beats/min; P = .016) during 66-second OFF-time and to 4.07 mVs (95% CI 2.42-5.72 mVs; P = .037) and 114 beats/min (95% CI 83-146 beats/min; P = .039) during 3-minute OFF-time. VNS increased the frequencies of prolonged (>3 seconds) pauses during AF. TH staining showed large confluent areas of damage in the left SG, characterized by pyknotic nuclei, reduced TH staining, increased percentage of TH-negative ganglion cells, and positive TUNEL staining. Occasional TUNEL-positive ganglion cells were also observed in the right SG.VNS damaged the SG, leading to reduced SGNA and better rate control during persistent AF.


PubMed | Chang Gung University, Riley Heart Research Center, Seoul National University, Indiana University and 5 more.
Type: Journal Article | Journal: Heart rhythm | Year: 2016

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).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.Optical mapping was used to study the membrane potential of the right atrium in Langendorff perfused Dct(-/-) (n = 9) and Dct(+/-) (n = 9) mice.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.Apamin-sensitive SK current upregulation in Dct(-/-) mice plays an important role in the mechanism of AA.


Barnes R.M.,Wells Center for Pediatric Research | Firulli B.A.,Wells Center for Pediatric Research | Vandusen N.J.,Wells Center for Pediatric Research | Morikawa Y.,Tulane University | And 5 more authors.
Circulation Research | Year: 2011

Rationale: The basic helix-loop-helix (bHLH) transcription factors Hand1 and Hand2 are essential for embryonic development. Given their requirement for cardiogenesis, it is imperative to determine their impact on cardiovascular function. Objective: To deduce the role of Hand2 within the epicardium. Zmethod and Results: We engineered a Hand1 allele expressing Cre recombinase. Cardiac Hand1 expression is largely limited to cells of the primary heart field, overlapping little with Hand2 expression. Hand1 is expressed within the septum transversum, and the Hand1 lineage marks the proepicardial organ and epicardium. To examine Hand factor functional overlap, we conditionally deleted Hand2 from Hand1-expressing cells. Hand2 mutants display defective epicardialization and fail to form coronary arteries, coincident with altered extracellular matrix deposition and Pdgfr expression. Conclusions: These data demonstrate a hierarchal relationship whereby transient Hand1 septum transversum expression defines epicardial precursors that are subsequently dependent on Hand2 function. © 2011 American Heart Association, Inc.


Zhang W.,Peking Union Medical College | Zhang W.,Riley Heart Research Center | Qu X.,Peking Union Medical College | Chen B.,University of Iowa | And 21 more authors.
Circulation | Year: 2016

Background - β-Adrenergic receptors (βARs) play paradoxical roles in the heart. On one hand, βARs augment cardiac performance to fulfill the physiological demands, but on the other hand, prolonged activations of βARs exert deleterious effects that result in heart failure. The signal transducer and activator of transcription 3 (STAT3) plays a dynamic role in integrating multiple cytokine signaling pathways in a number of tissues. Altered activation of STAT3 has been observed in failing hearts in both human patients and animal models. Our objective is to determine the potential regulatory roles of STAT3 in cardiac βAR-mediated signaling and function. Methods and Results - We observed that STAT3 can be directly activated in cardiomyocytes by β-adrenergic agonists. To follow up this finding, we analyzed βAR function in cardiomyocyte-restricted STAT3 knockouts and discovered that the conditional loss of STAT3 in cardiomyocytes markedly reduced the cardiac contractile response to acute βAR stimulation, and caused disengagement of calcium coupling and muscle contraction. Under chronic β-adrenergic stimulation, Stat3cKO hearts exhibited pronounced cardiomyocyte hypertrophy, cell death, and subsequent cardiac fibrosis. Biochemical and genetic data supported that Gαs and Src kinases are required for βAR-mediated activation of STAT3. Finally, we demonstrated that STAT3 transcriptionally regulates several key components of βAR pathway, including β1AR, protein kinase A, and T-type Ca2+ channels. Conclusions - Our data demonstrate for the first time that STAT3 has a fundamental role in βAR signaling and functions in the heart. STAT3 serves as a critical transcriptional regulator for βAR-mediated cardiac stress adaption, pathological remodeling, and heart failure. © 2015 American Heart Association, Inc.


Lee S.-H.,Beth Israel Deaconess Medical Center | Lee S.-H.,Catholic University of Korea | Huang H.,Beth Israel Deaconess Medical Center | Huang H.,East Carolina University | And 10 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2014

Rho kinase (ROCK) isoforms regulate insulin signaling and glucose metabolism negatively or positively in cultured cell lines and skeletal muscle. However, the in vivo function of the ROCK1 isoform in adipose tissue has not been addressed. To determine the specific role of the adipose ROCK1 isoform in the development of insulin resistance and obesity, mice lacking ROCK1 in adipose tissue globally or selectively were studied. Here, we show that insulin's ability to activate IRS-1/PI3K/Akt signaling was greatly enhanced in adipose tissue of ROCK1-/- mice compared with wild-type mice. These effects resulted from the inhibitory effect of ROCK1 on insulin receptor action, as evidenced by the fact that IR tyrosine phosphorylation was abolished in ROCK1-/- MEF cells when ROCK1 was reexpressed. Consistently, adipose-specific disruption of ROCK1 increased IR tyrosine phosphorylation in adipose tissue and modestly improved sensitivity to insulin in obese mice induced by high-fat feeding. This effect is independent of any changes in adiposity, number or size of adipocytes, and metabolic parameters, including glucose, insulin, leptin, and triglyceride levels, demonstrating a minimal effect of adipose ROCK1 on whole body metabolism. Enzymatic activity of ROCK1 in adipose tissue remained ~50%, which likely originated from the fraction of stromal vascular cells, suggesting involvement of these cells for adipose metabolic regulation. Moreover, ROCK isoform activities were increased in adipose tissue of diet-induced or genetically obese mice. These data suggest that adipose ROCK1 isoform plays an inhibtory role for the regulation of insulin sensitivity in diet-induced obesity in vivo. © 2014 the American Physiological Society.


Holler K.L.,University of Toledo | Hendershot T.J.,University of Toledo | Troy S.E.,University of Toledo | Vincentz J.W.,Riley Heart Research Center | And 2 more authors.
Developmental Biology | Year: 2010

The basic helix-loop-helix DNA binding protein Hand2 has critical functions in cardiac development both in neural crest-derived and mesoderm-derived structures. Targeted deletion of Hand2 in the neural crest has allowed us to genetically dissect Hand2-dependent defects specifically in outflow tract and cardiac cushion independent of Hand2 functions in mesoderm-derived structures. Targeted deletion of Hand2 in the neural crest results in misalignment of the aortic arch arteries and outflow tract, contributing to development of double outlet right ventricle (DORV) and ventricular septal defects (VSD). These neural crest-derived developmental anomalies are associated with altered expression of Hand2-target genes we have identified by gene profiling. A number of Hand2 direct target genes have been identified using ChIP and ChIP-on-chip analyses. We have identified and validated a number of genes related to cell migration, proliferation/cell cycle and intracellular signaling whose expression is affected by Hand2 deletion in the neural crest and which are associated with development of VSD and DORV. Our data suggest that Hand2 is a multifunctional DNA binding protein affecting expression of target genes associated with a number of functional interactions in neural crest-derived cells required for proper patterning of the outflow tract, generation of the appropriate number of neural crest-derived cells for elongation of the conotruncus and cardiac cushion organization. Our genetic model has made it possible to investigate the molecular genetics of neural crest contributions to outflow tract morphogenesis and cell differentiation. © 2010 Elsevier Inc.


Lu X.-L.,Harbin Medical University | Lu X.-L.,Riley Heart Research Center | Lu X.-L.,Indiana University | Xu W.-X.,Harbin Medical University | And 11 more authors.
International Journal of Biological Sciences | Year: 2013

Nodose ganglia are composed of A-, Ah- and C-type neurons. Despite their important roles in regulating visceral afferent function, including cardiovascular, pulmonary, and gastrointestinal homeostasis, information about subtype-specific expression, molecular identity, and function of individual ion transporting proteins is scarce. Although experiments utilizing the sliced ganglion preparation have provided valuable insights into the electrophysiological properties of nodose ganglion neuron subtypes, detailed characterization of their electrical phenotypes will require measurements in isolated cells. One major unresolved problem, however, is the difficulty to unambiguously identify the subtype of isolated nodose ganglion neurons without current-clamp recording, because the magnitude of conduction velocity in the corresponding afferent fiber, a reliable marker to discriminate subtypes in situ, can no longer be determined. Here, we present data supporting the notion that application of an algorithm regarding to microscopic structural characteristics, such as neuron shape evaluated by the ratio between shortest and longest axis, neuron surface characteristics, like membrane roughness, and axon attachment, enables specific and sensitive subtype identification of acutely dissociated rat nodose ganglion neurons, by which the accuracy of identification is further validated by electrophysiological markers and overall positive predictive rates is 89.26% (90.04%, 76.47%, and 98.21% for A-, Ah, and C-type, respectively). This approach should aid in gaining insight into the molecular correlates underlying phenotypic heterogeneity of nodose ganglia. Additionally, several critical points that help for neuron identification and afferent conduction calibration are also discussed. © Ivyspring International Publisher.


Shi J.,Riley Heart Research Center | Zhang L.,Riley Heart Research Center | Zhang Y.-W.,Riley Heart Research Center | Surma M.,Riley Heart Research Center | And 4 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2012

Doxorubicin is a highly effective chemotherapeutic agent used for treating a wide spectrum of tumors, but its usage is limited because of its dose-dependent cardiotoxicity, especially in pediatric patients. Accumulating evidence indicates that caspase-dependent apoptosis contributes to the cardiotoxicity of doxorubicin. However, less attention has been paid to the effects of age on doxorubicin-induced apoptosis signaling in myocardium. This study focused on investigating differential apoptotic sensitivity between neonatal and adult myocardium, in particular, between neonatal and adult cardiomyocytes in vivo. Our results show that caspase-3 activity in normal mouse hearts decreased by ≥20-fold within the first 3 wk after birth, associated with a rapid downregulation in the expression of key proapoptotic proteins in intrinsic and extrinsic pathways. This rapid downregulation of caspase-3 activity was confirmed by immunostaining for cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP-mediated nick-end label staining. Doxorubicin treatment induced a dose-dependent increase in caspase-3 activity and apoptosis in neonatal mouse hearts, and both caspase-8 and caspase-9 activations were involved. Using transgenic mice with a nuclear localized LacZ reporter gene to label cardiomyocytes in vivo, we observed a fourfold higher level of doxorubicininduced cardiomyocyte apoptosis in 1-wk-old mice compared with that in 3-wk-old mice. This study points to a major difference in apoptotic signaling in doxorubicin cardiotoxicity between neonatal and adult mouse hearts and reveals a critical transition from high to low susceptibility to doxorubicin-induced apoptosis during postnatal heart maturation. © 2012 the American Physiological Society.

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