@article{nokey,

title = {GJA1-20k and Mitochondrial Dynamics.},

author = {Shimura D, Shaw RM},

url = {https://www.frontiersin.org/articles/10.3389/fphys.2022.867358/full},

doi = {10.3389/fphys.2022.867358},

year  = {2022},

date = {2022-04-26},

urldate = {2022-04-26},

journal = {Front. Physiol.},

volume = {13: 867358.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Removal of an Internal Translational Start Site from mRNA While Retaining Expression of the Full-Length Protein.},

author = {Shimura D; Hunter J; Katsumata M, Shaw RM},

doi = {10.3791/63405},

year  = {2022},

date = {2022-03-16},

urldate = {2022-03-16},

journal = {J Vis Exp (JoVE)},

number = {(181): e63405},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Huntington’s disease skeletal muscle has altered T-tubules},

author = {Khan MS, Shaw RM},

issn = {Online Issn: 1540-7748},

year  = {2021},

date = {2021-05-12},

urldate = {2021-05-12},

journal = {JGP Journal of General Physiology},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Protective mitochondrial fission induced by stress responsive protein GJA1-20k.},

author = {Shimura D; Neubel E; Baum R; Valdez SE; Xiao X; Warren JS; Palatinus JA; Hong T; Rutter J, Shaw RM },

editor = {Shimura D, Neubel E, Baum R, Valdez SE, Xiao X, Warren JS, Palatinus JA, Hong T, Rutter J, },

url = {https://elifesciences.org/articles/69207},

doi = { 10.7554/eLife.69207},

year  = {2021},

date = {2021-04-27},

urldate = {2021-04-27},

journal = {eLife. },

volume = {10: e69207},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Ion Channel Trafficking in the Heart},

author = {Shaw RM,},

year  = {2021},

date = {2021-04-02},

urldate = {2021-04-02},

journal = {CARDIAC ELECTROPHYSIOLOGY},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {A role for connexin-43 in Duchenne muscular dystrophy cardiomyopathy},

author = {Shaw RM, Saffitz JE },

year  = {2021},

date = {2021-04-02},

urldate = {2021-04-02},

journal = {J Clin Invest},

volume = {130(4), 1608-1610.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{,

title = {cBIN1 Score (CS) identifies ambulatory HFrEF patients and predicts cardiovascular events},

author = {Hitzeman TC and Xie Y and Zadikany RH and Nikolova AP and Baum R and Xu B and Agvanian S and Melmed GY and McGovern DT and Geft DR and Chang DH and Moriguchi JD and Hage A and Azarbal B and Czer LS and Kittleson MM and Patel JK and Wu AHB and Kobashigawa JA and Hamilton M and Hong TT and Shaw RM.},

year  = {2020},

date = {2020-03-03},

journal = {Front Physiology},

volume = {11},

number = {503},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{,

title = {Auxiliary Trafficking Subunit GJA1-20k Protects Connexin43 from Degradation and Limits Ventricular Arrhythmias},

author = {Xiao, S and Shimura D and Baum R and Hernandez DM and Agvanian S and Nagaoka Y and Katsumata M and Lampe PD and Kleber AG and Hong T and Shaw RM.},

year  = {2020},

date = {2020-03-03},

journal = {JCI},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{,

title = {In Mice Subjected to Chronic Stress, Exogenous cBIN1 Preserves Calcium Handling Machinery and Cardiac Function},

author = {Liu Y and Zhou K and Li J and Agvanian S and Caldaruse A and Shaw S and Hitzeman TC and Shaw RM and Hong TT.},

year  = {2020},

date = {2020-03-02},

journal = {JACC},

abstract = {Heart failure is an important, and growing, cause of morbidity and mortality. Half of patients with heart failure have preserved ejection fraction, for whom therapeutic options are limited. Here we report that cardiac bridging integrator 1 gene therapy to maintain subcellular membrane compartments within cardiomyocytes can stabilize intracellular distribution of calcium-handling machinery, preserving diastolic function in hearts stressed by chronic beta agonist stimulation and pressure overload. The study identifies that maintenance of intracellular architecture and, in particular, membrane microdomains at t-tubules, is important in the setting of sympathetic stress. Stabilization of membrane microdomains may be a pathway for future therapeutic development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32244859,

title = {An Alternatively Translated Connexin 43 Isoform, GJA1-11k, Localizes to the Nucleus and Can Inhibit Cell Cycle Progression},

author = {Epifantseva I and Xiao S and Baum RE and Kleber AG and Hong T and Shaw RM },

year  = {2020},

date = {2020-03-01},

journal = {Biomolecules},

volume = {10},

number = {3},

abstract = {Connexin 43 (Cx43) is a gap junction protein that assembles at the cell border to form intercellular gap junction (GJ) channels which allow for cell-cell communication by facilitating the rapid transmission of ions and other small molecules between adjacent cells. Non-canonical roles of Cx43, and specifically its C-terminal domain, have been identified in the regulation of Cx43 trafficking, mitochondrial preconditioning, cell proliferation, and tumor formation, yet the mechanisms are still being explored. It was recently identified that up to six truncated isoforms of Cx43 are endogenously produced via alternative translation from internal start codons in addition to full length Cx43, all from the same mRNA produced by the gene GJA1. GJA1-11k, the 11kDa alternatively translated isoform of Cx43, does not have a known role in the formation of gap junction channels, and little is known about its function. Here, we report that over expressed GJA1-11k, unlike the other five truncated isoforms, preferentially localizes to the nucleus in HEK293FT cells and suppresses cell growth by limiting cell cycle progression from the G0/G1 phase to the S phase. Furthermore, these functions are independent of the channel-forming full-length Cx43 isoform. Understanding the apparently unique role of GJA1-11k and its generation in cell cycle regulation may uncover a new target for affecting cell growth in multiple disease models.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32091412,

title = {A role for connexin-43 in Duchenne muscular dystrophy cardiomyopathy},

author = {Shaw RM and Saffitz JE},

year  = {2019},

date = {2019-12-26},

journal = {J. Clin. Invest.},

volume = {130},

number = {4},

pages = {1608--1610},

abstract = {The cardiomyopathy of Duchenne muscular dystrophy (DMD) is an important cause of morbidity and mortality in affected males with this dreaded muscle disease. Previous studies have implicated changes in expression and subcellular localization of connexin-43 (Cx43), the major ventricular gap junction protein, in DMD cardiomyopathy. In this issue of the JCI, Himelman et al. explore how hypophosphorylation of Cx43 at a triplet of serine residues (S325/S328/S330) in the regulatory C-terminus contributes to multiple features of the cardiomyopathy phenotype. Using a mouse model of DMD cardiomyopathy in which phosphomimetic glutamic acids are substituted for serines at these residues in Cx43, Himelman et al. observed reduced gap junction remodeling and lateralization of Cx43 immunosignals, protection against isoproterenol-induced arrhythmias, and improved Ca2+ homeostasis. This study contributes to the understanding of pathologic Cx43 remodeling and encourages further research into developing strategic interventions to mitigate cardiac dysfunction and arrhythmias in DMD patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31876897,

title = {Correlating Cardiac Origin Neurohormonal Stress Levels With Heart Failure Outcomes},

author = {Shaw RM},

year  = {2019},

date = {2019-12-01},

journal = {JAMA Cardiol},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31518204,

title = {Letter by Nikolova et al Regarding Article, ‘Heart failure with preserved ejection fraction in perspective},

author = {Nikolova AP and Hong T and Shaw RM},

year  = {2019},

date = {2019-01-01},

journal = {Circ. Res.},

volume = {125},

number = {4},

pages = {e24-e25},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31172804,

title = {Heart failure: distinguishing failing myocardium from volume overload},

author = {Zadikany RH and Hong T and Shaw RM},

year  = {2019},

date = {2019-01-01},

journal = {Biomark Med},

volume = {13},

number = {9},

pages = {697--700},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30471985,

title = {Editorial commentary: Extracellular vesicles in cardiovascular diagnosis and therapy},

author = {Hong T and Shaw RM},

year  = {2019},

date = {2019-01-01},

journal = {Trends Cardiovasc. Med.},

volume = {29},

number = {6},

pages = {324--325},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30442291,

title = {The Clinical Course of a Genetic Dilated Cardiomyopathy: Letting the Cat Out of the BAG3},

author = {Shaw RM and Nikolova AP},

year  = {2018},

date = {2018-01-01},

journal = {J. Am. Coll. Cardiol.},

volume = {72},

number = {20},

pages = {2482--2484},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30383171,

title = {Association of a Novel Diagnostic Biomarker, the Plasma Cardiac Bridging Integrator 1 Score, With Heart Failure With Preserved Ejection Fraction and Cardiovascular Hospitalization},

author = {Nikolova AP, Hitzeman TC, Baum R, Caldaruse A, Agvanian S, Xie Y, Geft DR, Chang DH, Moriguchi JD, Hage A, Azarbal B, Czer LS, Kittleson MM, Patel JK, Wu AHB, Kobashigawa JA, Hamilton M, Hong TT, Shaw RM},

year  = {2018},

date = {2018-01-01},

journal = {JAMA Cardiol},

volume = {3},

number = {12},

pages = {1206--1210},

abstract = {Transverse tubule remodeling is a hallmark of heart failure. Cardiac bridging integrator 1 (cBIN1) is a circulating membrane scaffolding protein that is essential for transverse tubule health, and its plasma level declines with disease. To determine if a cBIN1-derived score can serve as a diagnostic biomarker of heart failure with preserved ejection fraction (HFpEF). In this cohort study, the cBIN1 score (CS) was determined from enzyme-linked immunoabsorbent assay-measured plasma cBIN1 concentrations from study participants in an ambulatory heart failure clinic at Cedars-Sinai Medical Center. Consecutive patients with a confirmed diagnosis of heart failure with preserved ejection fraction (HFpEF; defined by a left ventricular ejection fraction ≥50%) were recruited from July 2014 to November 2015 and compared with age-matched and sex-matched healthy volunteers with no known cardiovascular diagnoses and participants with risk factors for heart failure but no known HFpEF. Baseline characteristics and 1-year longitudinal clinical information were obtained through electronic medical records. Data analysis occurred from November 2016 to November 2017. The analysis examined the ability of the CS and N-terminal pro-B-type natriuretic peptide (NT-proBNP) results to differentiate among patients with HFpEF, healthy control participants, and control participants with risk factors for heart failure. We further explored the association of the CS with future cardiovascular hospitalizations. A total of 52 consecutive patients with a confirmed diagnosis of HFpEF were enrolled (mean [SD] age, 57 [15] years; 33 [63%] male). The CS values are significantly higher in the patients with HFpEF (median [interquartile range (IQR)], 1.85 [1.51-2.28]) than in the 2 control cohorts (healthy control participants: median [IQR], -0.03 [-0.48 to 0.41]; control participants with risk factors only: median [IQR], -0.08 [-0.75 to 0.42]; P < .001). For patients with HFpEF, the CS outperforms NT-proBNP when the comparator group was either healthy control participants (CS: area under curve [AUC], 0.98 [95% CI, 0.96-1.00]; NT-proBNP level: AUC, 0.93 [95% CI, 0.88-0.99]; P < .001) or those with risk factors (CS: AUC, 0.98 [95% CI, 0.97-1.00]; NT-proBNP: AUC, 0.93 [95% CI, 0.88-0.99]; P < .001). Kaplan-Meier analysis of 1-year cardiovascular hospitalizations adjusted for age, sex, body mass index, and NT-proBNP levels reveals that patients with HFpEF with CS greater than or equal to 1.80 have a hazard ratio of 3.8 (95% CI, 1.3-11.2; P = .02) for hospitalizations compared with those with scores less than 1.80. If further validated, the plasma CS, a marker of transverse tubule dysfunction, may serve as a biomarker of cardiomyocyte remodeling that has the potential to aide in the diagnosis of HFpEF.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30333316,

title = {Stress response protein GJA1-20k promotes mitochondrial biogenesis, metabolic quiescence, and cardioprotection against ischemia/reperfusion injury},

author = {Basheer WA, Fu Y, Shimura D, Xiao S, Agvanian S, Hernandez DM, Hitzeman TC, Hong TT, Shaw RM},

year  = {2018},

date = {2018-01-01},

journal = {JCI Insight},

volume = {3},

number = {20},

abstract = {Connexin 43 (Cx43), a product of the GJA1 gene, is a gap junction protein facilitating intercellular communication between cardiomyocytes. Cx43 protects the heart from ischemic injury by mechanisms that are not well understood. GJA1 mRNA can undergo alternative translation, generating smaller isoforms in the heart, with GJA1-20k being the most abundant. Here, we report that ischemic and ischemia/reperfusion (I/R) injuries upregulate endogenous GJA1-20k protein in the heart, which targets to cardiac mitochondria and associates with the outer mitochondrial membrane. Exploring the functional consequence of increased GJA1-20k, we found that AAV9-mediated gene transfer of GJA1-20k in mouse hearts increases mitochondrial biogenesis while reducing mitochondrial membrane potential, respiration, and ROS production. By doing so, GJA1-20k promotes a protective mitochondrial phenotype, as seen with ischemic preconditioning (IPC), which also increases endogenous GJA1-20k in heart lysates and mitochondrial fractions. As a result, AAV9-GJA1-20k pretreatment reduces myocardial infarct size in mouse hearts subjected to in vivo ischemic injury or ex vivo I/R injury, similar to an IPC-induced cardioprotective effect. In conclusion, GJA1-20k is an endogenous stress response protein that induces mitochondrial biogenesis and metabolic hibernation, preconditioning the heart against I/R insults. Introduction of exogenous GJA1-20k is a putative therapeutic strategy for patients undergoing anticipated ischemic injury.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29661709,

title = {Editorial commentary: Are cytokines ready for prime time? Insights from markers and trials},

author = {Nikolova AP, Shaw RM},

year  = {2018},

date = {2018-01-01},

journal = {Trends Cardiovasc. Med.},

volume = {28},

number = {6},

pages = {380--381},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29420963,

title = {A Surprising Noncanonical Role for Calcineurin in Pressure-Induced Cardiac Hypertrophy},

author = {Shaw RM and Nikolova AP},

year  = {2018},

date = {2018-01-01},

journal = {J. Am. Coll. Cardiol.},

volume = {71},

number = {6},

pages = {668--669},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28576298,

title = {Intracellular trafficking pathways of Cx43 gap junction channels},

author = {Epifantseva I, Shaw RM},

year  = {2018},

date = {2018-01-01},

journal = {Biochim Biophys Acta Biomembr},

volume = {1860},

number = {1},

pages = {40--47},

abstract = {Gap Junction (GJ) channels, including the most common Connexin 43 (Cx43), have fundamental roles in excitable tissues by facilitating rapid transmission of action potentials between adjacent cells. For instance, synchronization during each heartbeat is regulated by these ion channels at the cardiomyocyte cell-cell border. Cx43 protein has a short half-life, and rapid synthesis and timely delivery of those proteins to particular subdomains are crucial for the cellular organization of gap junctions and maintenance of intracellular coupling. Impairment in gap junction trafficking contributes to dangerous complications in diseased hearts such as the arrhythmias of sudden cardiac death. Of recent interest are the protein-protein interactions with the Cx43 carboxy-terminus. These interactions have significant impact on the full length Cx43 lifecycle and also contribute to trafficking of Cx43 as well as possibly other functions. We are learning that many of the known non-canonical roles of Cx43 can be attributed to the recently identified six endogenous Cx43 truncated isoforms which are produced by internal translation. In general, alternative translation is a new leading edge for proteome expansion and therapeutic drug development. This review highlights recent mechanisms identified in the trafficking of gap junction channels, involvement of other proteins contributing to the delivery of channels to the cell-cell border, and understanding of possible roles of the newly discovered alternatively translated isoforms in Cx43 biology. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29163229,

title = {Cx43 Isoform GJA1-20k Promotes Microtubule Dependent Mitochondrial Transport},

author = {Fu Y, Zhang SS, Xiao S, Basheer WA, Baum R, Epifantseva I, Hong TT, Shaw RM},

year  = {2017},

date = {2017-01-01},

journal = {Front Physiol},

volume = {8},

pages = {905},

abstract = {Connexin 43 (Cx43, encoded by GJA1) is a cell-cell communication gap junction protein expressed in all organ systems. It was recently found that GJA1 mRNA undergoes alternative translation to generate N-terminal truncated isoforms, of which GJA1-20k is the most abundant. Here we report a surprising finding that, unlike full length GJA1-43k, GJA1-20k has a strong tropism for mitochondria. Exploring function, we found that GJA1-20k appears to be an organelle chaperone and that overexpression of GJA1-20k is sufficient to rescue mitochondrial localization to the cell periphery upon exposure to hydrogen peroxide, which effectively limits the network fragmentation that occurs with oxidative stress. By high-resolution fluorescent imaging and electron microscopy, we determined that GJA1-20k is enriched at the interface between mitochondria and microtubules, appearing to load organelles for transport. Mutagenesis experiments revealed that although the microtubule-binding domain (MTBD) in GJA1-20k is not necessary for protein localization to mitochondria, the MTBD is essential for GJA1-20k to facilitate mitochondrial transport and maintain mitochondrial localization at the periphery. These results reveal an unexpected role for the alternatively translated isoform of the Cx43 gap junction protein, GJA1-20k, which is to facilitate microtubule-based mitochondrial transport and to maintain mitochondrial network integrity during cellular stress.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28923791,

title = {GJA1-20k Arranges Actin to Guide Cx43 Delivery to Cardiac Intercalated Discs},

author = {Basheer WA, Xiao S, Epifantseva I, Fu Y, Kleber AG, Hong TT, Shaw RM},

year  = {2017},

date = {2017-01-01},

journal = {Circ. Res.},

volume = {121},

number = {9},

pages = {1069--1080},

abstract = {Delivery of Cx43 (connexin 43) to the intercalated disc is a continuous and rapid process critical for intercellular coupling. By a pathway of targeted delivery involving microtubule highways, vesicles of Cx43 hemichannels are efficiently trafficked to adherens junctions at intercalated discs. It has also been identified that actin provides rest stops for Cx43 forward trafficking and that Cx43 has a 20 kDa internally translated small C terminus isoform, GJA1-20k (Gap Junction Protein Alpha 1- 20 kDa), which is required for full-length Cx43 trafficking, but by an unknown mechanism. We explored the mechanism by which the GJA1-20k isoform is required for full-length Cx43 forward trafficking to intercalated discs. Using an in vivo Adeno-associated virus serotype 9-mediated gene transfer system, we confirmed in whole animal that GJA1-20k markedly increases endogenous myocardial Cx43 gap junction plaque size at the intercalated discs. In micropatterned cell pairing systems, we found that exogenous GJA1-20k expression stabilizes filamentous actin without affecting actin protein expression and that GJA1-20k complexes with both actin and tubulin. We also found that filamentous actin regulates microtubule organization as inhibition of actin polymerization with a low dose of latrunculin A disrupts the targeting of microtubules to cell-cell junctions. GJA1-20k protects actin filament from latrunculin A disruption, preserving microtubule trajectory to the cell-cell border. For therapeutic implications, we found that prior in vivo Adeno-associated virus serotype 9-mediated gene delivery of GJA1-20k to the heart protects Cx43 localization to the intercalated discs against acute ischemic injury. The internally translated GJA1-20k isoform stabilizes actin filaments, which guides growth trajectories of the Cx43 microtubule trafficking machinery, increasing delivery of Cx43 hemichannels to cardiac intercalated discs. Exogenous GJA1-20k helps to maintain cell-cell coupling in instances of anticipated myocardial ischemia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28806752,

title = {The ESCRT-III pathway facilitates cardiomyocyte release of cBIN1-containing microparticles},

author = {Xu B, Fu Y, Liu Y, Agvanian S, Shaw RM, Hong TT},

year  = {2017},

date = {2017-01-01},

journal = {PLoS Biol.},

volume = {15},

number = {8},

pages = {e2002354},

abstract = {Microparticles (MPs) are cell-cell communication vesicles derived from the cell surface plasma membrane, although they are not known to originate from cardiac ventricular muscle. In ventricular cardiomyocytes, the membrane deformation protein cardiac bridging integrator 1 (cBIN1 or BIN1+13+17) creates transverse-tubule (t-tubule) membrane microfolds, which facilitate ion channel trafficking and modulate local ionic concentrations. The microfold-generated microdomains continuously reorganize, adapting in response to stress to modulate the calcium signaling apparatus. We explored the possibility that cBIN1-microfolds are externally released from cardiomyocytes. Using electron microscopy imaging with immunogold labeling, we found in mouse plasma that cBIN1 exists in membrane vesicles about 200 nm in size, which is consistent with the size of MPs. In mice with cardiac-specific heterozygous Bin1 deletion, flow cytometry identified 47% less cBIN1-MPs in plasma, supporting cardiac origin. Cardiac release was also evidenced by the detection of cBIN1-MPs in medium bathing a pure population of isolated adult mouse cardiomyocytes. In human plasma, osmotic shock increased cBIN1 detection by enzyme-linked immunosorbent assay (ELISA), and cBIN1 level decreased in humans with heart failure, a condition with reduced cardiac muscle cBIN1, both of which support cBIN1 release in MPs from human hearts. Exploring putative mechanisms of MP release, we found that the membrane fission complex endosomal sorting complexes required for transport (ESCRT)-III subunit charged multivesicular body protein 4B (CHMP4B) colocalizes and coimmunoprecipitates with cBIN1, an interaction enhanced by actin stabilization. In HeLa cells with cBIN1 overexpression, knockdown of CHMP4B reduced the release of cBIN1-MPs. Using truncation mutants, we identified that the N-terminal BAR (N-BAR) domain in cBIN1 is required for CHMP4B binding and MP release. This study links the BAR protein superfamily to the ESCRT pathway for MP biogenesis in mammalian cardiac ventricular cells, identifying elements of a pathway by which cytoplasmic cBIN1 is released into blood.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28596164,

title = {CASAAV Technology to Examine Regulators of Heart Failure: Cause or Effect},

author = {Fu Y and Shaw RM},

year  = {2017},

date = {2017-01-01},

journal = {Circ. Res.},

volume = {120},

number = {12},

pages = {1846--1848},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27881552,

title = {Cardiac T-Tubule Microanatomy and Function},

author = {Hong T, Shaw RM},

year  = {2017},

date = {2017-01-01},

journal = {Physiol. Rev.},

volume = {97},

number = {1},

pages = {227--252},

abstract = {Unique to striated muscle cells, transverse tubules (t-tubules) are membrane organelles that consist of sarcolemma penetrating into the myocyte interior, forming a highly branched and interconnected network. Mature t-tubule networks are found in mammalian ventricular cardiomyocytes, with the transverse components of t-tubules occurring near sarcomeric z-discs. Cardiac t-tubules contain membrane microdomains enriched with ion channels and signaling molecules. The microdomains serve as key signaling hubs in regulation of cardiomyocyte function. Dyad microdomains formed at the junctional contact between t-tubule membrane and neighboring sarcoplasmic reticulum are critical in calcium signaling and excitation-contraction coupling necessary for beat-to-beat heart contraction. In this review, we provide an overview of the current knowledge in gross morphology and structure, membrane and protein composition, and function of the cardiac t-tubule network. We also review in detail current knowledge on the formation of functional membrane subdomains within t-tubules, with a particular focus on the cardiac dyad microdomain. Lastly, we discuss the dynamic nature of t-tubules including membrane turnover, trafficking of transmembrane proteins, and the life cycles of membrane subdomains such as the cardiac BIN1-microdomain, as well as t-tubule remodeling and alteration in diseased hearts. Understanding cardiac t-tubule biology in normal and failing hearts is providing novel diagnostic and therapeutic opportunities to better treat patients with failing hearts.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{,

title = {The ‘Tail’ of Connexin43: An Unexpected Journey from Alternative Translation to Trafficking},

author = {Basheer WA and Shaw RM},

year  = {2016},

date = {2016-03-03},

journal = {Biochimica et Biophysica Acta},

volume = {1863},

number = {1848-56},

abstract = {Rationale 

Delivery of connexin 43 (Cx43) to the intercalated disc is a continuous and rapid process critical for intercellular coupling. By a pathway of targeted delivery involving microtubule highways, vesicles of Cx43 hemichannels are efficiently trafficked to adherens junctions at intercalated discs. It has also been identified that actin provides rest stops for Cx43 forward trafficking, and that Cx43 has a 20kDa internally translated small C-terminus isoform (GJA1-20k) which is required for full-length Cx43 trafficking, but by an unknown mechanism. 

Objective 

We explored the mechanism by which the GJA1-20k isoform is required for full-length Cx43 forward trafficking to intercalated discs. 

Methods and Results 

Using an in-vivo AAV9-mediated gene transfer system, we confirmed in whole animal that GJA1-20k markedly increases endogenous myocardial Cx43 gap junction plaque size at the intercalated discs. In micropatterned cell pairing systems, we found that exogenous GJA1-20k expression stabilizes filamentous actin (F-actin) without affecting actin protein expression, and that GJA1-20k complexes with both actin and tubulin. We also found that F-actin regulates microtubule organization as inhibition of actin polymerization with a low dose of latrunculin A (LatA) disrupts the targeting of microtubules to cell-cell junctions. GJA1-20k protects actin filament from LatA disruption, preserving microtubule trajectory to the cell-cell border. For therapeutic implications, we found that prior in vivo AAV9-mediated gene delivery of GJA1-20k to the heart protects Cx43 localization to the intercalated discs against acute ischemic injury. 

Conclusions 

The internally translated GJA1-20k isoform stabilizes actin filaments which guides growth trajectories of the Cx43 microtubule trafficking machinery, increasing delivery of Cx43 hemichannels to cardiac intercalated discs. Exogenous GJA1-20k helps to maintain cell-cell coupling in instances of anticipated myocardial ischemia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{,

title = {Ion Channel Trafficking},

author = {Hong T and Shaw RM},

year  = {2016},

date = {2016-03-03},

journal = {Ion Channels in Health and Disease},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27798760,

title = {Rad-deletion Phenocopies Tonic Sympathetic Stimulation of the Heart},

author = {Levitan BM, Manning JR, Withers CN, Smith JD, Shaw RM, Andres DA, Sorrell VL, Satin J},

year  = {2016},

date = {2016-01-01},

journal = {J Cardiovasc Transl Res},

volume = {9},

number = {5-6},

pages = {432--444},

abstract = {Sympathetic stimulation modulates L-type calcium channel (LTCC) gating to contribute to increased systolic heart function. Rad is a monomeric G-protein that interacts with LTCC. Genetic deletion of Rad (Rad-/-) renders LTCC in a sympathomimetic state. The study goal was to use a clinically inspired pharmacological stress echocardiography test, including analysis of global strain, to determine whether Rad-/- confers tonic positive inotropic heart function. Sarcomere dynamics and strain showed partial parallel isoproterenol (ISO) responsiveness for wild-type (WT) and for Rad-/-. Rad-/- basal inotropy was elevated compared to WT but was less responsiveness to ISO. Rad protein levels were lower in human patients with end-stage non-ischemic heart failure. These results show that Rad reduction provides a stable inotropic response rooted in sarcomere level function. Thus, reduced Rad levels in heart failure patients may be a compensatory response to need for increased output in the setting of HF. Rad deletion suggests a future therapeutic direction for inotropic support.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27266274,

title = {Cx43 and CaV1.2 Ion Channel Trafficking in Healthy and Diseased Myocardium},

author = {Basheer WA, Shaw RM},

year  = {2016},

date = {2016-01-01},

journal = {Circ Arrhythm Electrophysiol},

volume = {9},

number = {6},

pages = {e001357},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25649302,

title = {Cardiomyocyte protein trafficking: Relevance to heart disease and opportunities for therapeutic intervention},

author = {Xiao S, Shaw RM},

year  = {2015},

date = {2015-07-01},

journal = {Trends Cardiovasc. Med.},

volume = {25},

number = {5},

pages = {379--389},

abstract = {Cardiomyocytes, the individual contractile units of heart muscle, are long-lived and robust. Given the longevity of these cells, it can be easy to overlook their dynamic intracellular environment that contain rapid protein movements and frequent protein turnover. Critical gene transcription and protein translation occur continuously, as well as trafficking and localization of proteins to specific functional zones of cell membrane. As heart failure becomes an increasingly important clinical entity, growing numbers of investigative teams are examining the cell biology of healthy and diseased cardiomyocytes. In this review, we introduce the major architectural structures and types of protein movements within cardiac cells, and then review recent studies that explore the regulation of such movements. We conclude by introducing current translational directions of the basic studies with a focus on novel areas of therapeutic development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25772290,

title = {Na+ channel function, regulation, structure, trafficking and sequestration},

author = {Chen-Izu Y, Shaw RM, Pitt GS, Yarov-Yarovoy V, Sack JT, Maltsev VA, Deschenes I, Mohler PJ, Abriel H, Aldrich RW, Cannell MB, Catterall WA, Chazin WJ, Chiamvimonvat N, Grandi E, Hund TJ, Izu LT, Maier LS, Marionneau C, Rajamani S, Rasmusson RL, Sobie EA, Belardinelli L, Clancy CE, Bers DM},

year  = {2015},

date = {2015-03-01},

journal = {J. Physiol. (Lond.)},

volume = {593},

number = {6},

pages = {1347--1360},

abstract = {This paper is the second of a series of three reviews published in this issue resulting from the University of California Davis Cardiovascular Symposium 2014: Systems approach to understanding cardiac excitation-contraction coupling and arrhythmias: Na(+) channel and Na(+) transport. The goal of the symposium was to bring together experts in the field to discuss points of consensus and controversy on the topic of sodium in the heart. The present review focuses on Na(+) channel function and regulation, Na(+) channel structure and function, and Na(+) channel trafficking, sequestration and complexing.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25632042,

title = {Cytoskeleton regulation of ion channels},

author = {Fu Y, Xiao S, Hong TT, Shaw RM},

year  = {2015},

date = {2015-02-01},

journal = {Circulation},

volume = {131},

number = {8},

pages = {689--691},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25373772,

title = {Desmosomal hotspots, microtubule delivery, and cardiac arrhythmogenesis},

author = {Shaw RM},

year  = {2014},

date = {2014-06-04},

journal = {Dev. Cell},

volume = {31},

number = {2},

pages = {139--140},

abstract = {Microtubules can target proteins such as Connexin43 to plasma membrane subdomains. Patel et al. (2014) now show that the structural desmosome complex participates in targeted trafficking of membrane components through interactions between the microtubule network and the N terminus of desmoplakin, a region that is a pathogenic mutation hotspot.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24444605,

title = {A micropatterning approach for imaging dynamic Cx43 trafficking to cell-cell borders},

author = {Zhang SS, Hong SG, Kléber AG, Lee LP, and Shaw RM},

year  = {2014},

date = {2014-06-04},

journal = {FEBS Lett.},

volume = {588},

number = {8},

pages = {1439--1445},

abstract = {The precise expression and timely delivery of connexin 43 (Cx43) proteins to form gap junctions are essential for electrical coupling of cardiomyocytes. Growing evidence supports a cytoskeletal-based trafficking paradigm for Cx43 delivery directly to adherens junctions at the intercalated disc. A limitation of Cx43 localization assays in cultured cells, in which cell-cell contacts are essential, is the inability to control for cell geometry or reproducibly generate contact points. Here we present a micropatterned cell pairing system well suited for live microscopy to examine how the microtubule and actin cytoskeleton confer specificity to Cx43 trafficking to precisely defined cell-cell junctions. This system can be adapted for other cell types and used to study dynamic intracellular movements of other proteins important for cell-cell communication.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24836577,

title = {Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia},

author = {Hong T, Yang H, Zhang S, Cho HC, Kalashnikova M, Sun B, Zhang H, Bhargava A, Grabe M, Olgin J, Gorelik J, Marbán E, Jan LY, Shaw RM},

year  = {2014},

date = {2014-06-01},

journal = {Nat. Med.},

volume = {20},

number = {6},

pages = {624--632},

abstract = {Cardiomyocyte T tubules are important for regulating ion flux. Bridging integrator 1 (BIN1) is a T-tubule protein associated with calcium channel trafficking that is downregulated in failing hearts. Here we find that cardiac T tubules normally contain dense protective inner membrane folds that are formed by a cardiac isoform of BIN1. In mice with cardiac Bin1 deletion, T-tubule folding is decreased, which does not change overall cardiomyocyte morphology but leads to free diffusion of local extracellular calcium and potassium ions, prolonging action-potential duration and increasing susceptibility to ventricular arrhythmias. We also found that T-tubule inner folds are rescued by expression of the BIN1 isoform BIN1+13+17, which promotes N-WASP-dependent actin polymerization to stabilize the T-tubule membrane at cardiac Z discs. BIN1+13+17 recruits actin to fold the T-tubule membrane, creating a 'fuzzy space' that protectively restricts ion flux. When the amount of the BIN1+13+17 isoform is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered, and arrhythmia can result.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24612377,

title = {A 14-3-3 mode-1 binding motif initiates gap junction internalization during acute cardiac ischemia},

author = {Smyth JW, Zhang SS, Sanchez JM, Lamouille S, Vogan JM, Hesketh GG, Hong T, Tomaselli GF, Shaw RM},

year  = {2014},

date = {2014-06-01},

journal = {Traffic},

volume = {15},

number = {6},

pages = {684--699},

abstract = {Altered phosphorylation and trafficking of connexin 43 (Cx43) during acute ischemia contributes to arrhythmogenic gap junction remodeling, yet the critical sequence and accessory proteins necessary for Cx43 internalization remain unresolved. 14-3-3 proteins can regulate protein trafficking, and a 14-3-3 mode-1 binding motif is activated upon phosphorylation of Ser373 of the Cx43 C-terminus. We hypothesized that Cx43(Ser373) phosphorylation is important to pathological gap junction remodeling. Immunofluorescence in human heart reveals the enrichment of 14-3-3 proteins at intercalated discs, suggesting interaction with gap junctions. Knockdown of 14-3-3Ï„ in cell lines increases gap junction plaque size at cell-cell borders. Cx43(S373A) mutation prevents Cx43/14-3-3 complexing and stabilizes Cx43 at the cell surface, indicating avoidance of degradation. Using Langendorff-perfused mouse hearts, we detect phosphorylation of newly internalized Cx43 at Ser373 and Ser368 within 30 min of no-flow ischemia. Phosphorylation of Cx43 at Ser368 by protein kinase C and Ser255 by mitogen-activated protein kinase has previously been implicated in Cx43 internalization. The Cx43(S373A) mutant is resistant to phosphorylation at both these residues and does not undergo ubiquitination, revealing Ser373 phosphorylation as an upstream gatekeeper of a posttranslational modification cascade necessary for Cx43 internalization. Cx43(Ser373) phosphorylation is a potent target for therapeutic interventions to preserve gap junction coupling in the stressed myocardium.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24508725,

title = {Role for myosin-V motor proteins in the selective delivery of Kv channel isoforms to the membrane surface of cardiac myocytes},

author = {Schumacher-Bass SM, Vesely ED, Zhang L, Ryland KE, McEwen DP, Chan PJ, Frasier CR, McIntyre JC, Shaw RM, Martens JR},

year  = {2014},

date = {2014-03-01},

journal = {Circ. Res.},

volume = {114},

number = {6},

pages = {982--992},

abstract = {Kv1.5 (KCNA5) mediates the ultra-rapid delayed rectifier current that controls atrial action potential duration. Given its atrial-specific expression and alterations in human atrial fibrillation, Kv1.5 has emerged as a promising target for the treatment of atrial fibrillation. A necessary step in the development of novel agents that selectively modulate trafficking pathways is the identification of the cellular machinery controlling Kv1.5 surface density, of which little is yet known. To investigate the role of the unconventional myosin-V (MYO5A and MYO5B) motors in determining the cell surface density of Kv1.5. Western blot analysis showed MYO5A and MYO5B expression in the heart, whereas disruption of endogenous motors selectively reduced IKur current in adult rat cardiomyocytes. Dominant negative constructs and short hairpin RNA silencing demonstrated a role for MYO5A and MYO5B in the surface trafficking of Kv1.5 and connexin-43 but not potassium voltage-gated channel, subfamily H (eag-related), member 2 (KCNH2). Live-cell imaging of Kv1.5-GFP and retrospective labeling of phalloidin demonstrated motility of Kv1.5 vesicles on actin tracts. MYO5A participated in anterograde trafficking, whereas MYO5B regulated postendocytic recycling. Overexpression of mutant motors revealed a selective role for Rab11 in coupling MYO5B to Kv1.5 recycling. MYO5A and MYO5B control functionally distinct steps in the surface trafficking of Kv1.5. These isoform-specific trafficking pathways determine Kv1.5-encoded IKur in myocytes to regulate repolarizing current and, consequently, cardiac excitability. Therapeutic strategies that manipulate Kv1.5 selective trafficking pathways may prove useful in the treatment of arrhythmias.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24460200,

title = {Trafficking highways to the intercalated disc: new insights unlocking the specificity of connexin 43 localization},

author = {Zhang SS and Shaw RM},

year  = {2014},

date = {2014-02-01},

journal = {Cell Commun. Adhes.},

volume = {21},

number = {1},

pages = {43--54},

abstract = {With each heartbeat, billions of cardiomyocytes work in concert to propagate the electrical excitation needed to effectively circulate blood. Regulated expression and timely delivery of connexin proteins to form gap junctions at the specialized cell-cell contact region, known as the intercalated disc, is essential to ventricular cardiomyocyte coupling. We focus this review on several regulatory mechanisms that have been recently found to govern the lifecycle of connexin 43 (Cx43), the short-lived and most abundantly expressed connexin in cardiac ventricular muscle. The Cx43 lifecycle begins with gene expression, followed by oligomerization into hexameric channels, and then cytoskeletal-based transport toward the disc region. Once delivered, hemichannels interact with resident disc proteins and are organized to effect intercellular coupling. We highlight recent studies exploring regulation of Cx43 localization to the intercalated disc, with emphasis on alternatively translated Cx43 isoforms and cytoskeletal transport machinery that together regulate Cx43 gap junction coupling between cardiomyocytes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24311987,

title = {3-OST-7 regulates BMP-dependent cardiac contraction},

author = {Samson SC, Ferrer T, Jou CJ, Sachse FB, Shankaran SS, Shaw RM, Chi NC, Tristani-Firouzi M, Yost HJ},

year  = {2013},

date = {2013-12-01},

journal = {PLoS Biol.},

volume = {11},

number = {12},

pages = {e1001727},

abstract = {The 3-O-sulfotransferase (3-OST) family catalyzes rare modifications of glycosaminoglycan chains on heparan sulfate proteoglycans, yet their biological functions are largely unknown. Knockdown of 3-OST-7 in zebrafish uncouples cardiac ventricular contraction from normal calcium cycling and electrophysiology by reducing tropomyosin4 (tpm4) expression. Normal 3-OST-7 activity prevents the expansion of BMP signaling into ventricular myocytes, and ectopic activation of BMP mimics the ventricular noncontraction phenotype seen in 3-OST-7 depleted embryos. In 3-OST-7 morphants, ventricular contraction can be rescued by overexpression of tropomyosin tpm4 but not by troponin tnnt2, indicating that tpm4 serves as a lynchpin for ventricular sarcomere organization downstream of 3-OST-7. Contraction can be rescued by expression of 3-OST-7 in endocardium, or by genetic loss of bmp4. Strikingly, BMP misregulation seen in 3-OST-7 morphants also occurs in multiple cardiac noncontraction models, including potassium voltage-gated channel gene, kcnh2, affected in Romano-Ward syndrome and long-QT syndrome, and cardiac troponin T gene, tnnt2, affected in human cardiomyopathies. Together these results reveal 3-OST-7 as a key component of a novel pathway that constrains BMP signaling from ventricular myocytes, coordinates sarcomere assembly, and promotes cardiac contractile function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24210816,

title = {Autoregulation of connexin43 gap junction formation by internally translated isoforms},

author = {Smyth JW and Shaw RM},

year  = {2013},

date = {2013-11-01},

journal = {Cell Rep},

volume = {5},

number = {3},

pages = {611--618},

abstract = {During each heartbeat, intercellular electrical coupling via connexin43 (Cx43) gap junctions enables synchronous cardiac contraction. In failing hearts, impaired Cx43 trafficking reduces gap junction coupling, resulting in arrhythmias. Here we report that internal translation within Cx43 (GJA1) mRNA occurs, resulting in truncated isoforms that autoregulate Cx43 trafficking. We find that at least four truncated Cx43 isoforms occur in the human heart, with a 20 kDa isoform predominating. In-frame AUG codons within GJA1 mRNA are the translation initiation sites and their ablation arrests trafficking of full-length Cx43. The 20 kDa isoform is sufficient to rescue this trafficking defect in trans, suggesting it as a trafficking chaperone for Cx43. Limiting cap-dependent translation through inhibition of mTOR enhances truncated isoform expression, increasing Cx43 gap junction size. The results suggest that internal translation is a mechanism of membrane protein autoregulation and a potent target for therapies aimed at restoring normal electrical coupling in diseased hearts.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23417040,

title = {L-type calcium channel targeting and local signalling in cardiac myocytes},

author = {Shaw RM and Colecraft HM},

year  = {2013},

date = {2013-05-01},

journal = {Cardiovasc. Res.},

volume = {98},

number = {2},

pages = {177--186},

abstract = {In the heart, Ca(2+) influx via Ca(V)1.2 L-type calcium channels (LTCCs) is a multi-functional signal that triggers muscle contraction, controls action potential duration, and regulates gene expression. The use of LTCC Ca(2+) as a multi-dimensional signalling molecule in the heart is complicated by several aspects of cardiac physiology. Cytosolic Ca(2+) continuously cycles between ~100 nM and ~1 μM with each heartbeat due to Ca(2+) linked signalling from LTCCs to ryanodine receptors. This rapid cycling raises the question as to how cardiac myocytes distinguish the Ca(2+) fluxes originating through L-type channels that are dedicated to contraction from Ca(2+) fluxes originating from other L-type channels that are used for non-contraction-related signalling. In general, disparate Ca(2+) sources in cardiac myocytes such as current through differently localized LTCCs as well as from IP3 receptors can signal selectively to Ca(2+)-dependent effectors in local microdomains that can be impervious to the cytoplasmic Ca(2+) transients that drive contraction. A particular challenge for diversified signalling via cardiac LTCCs is that they are voltage-gated and, therefore, open and presumably flood their microdomains with Ca(2+) with each action potential. Thus spatial localization of Cav1.2 channels to different types of microdomains of the ventricular cardiomyocyte membrane as well as the existence of particular macromolecular complexes in each Cav1.2 microdomain are important to effect different types of Cav1.2 signalling. In this review we examine aspects of Cav1.2 structure, targeting and signalling in two specialized membrane microdomains--transverse tubules and caveolae.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{,

title = {Performance of the REVEAL model in WHO Group 2 to 5 pulmonary hypertension: application beyond pulmonary arterial hypertension.},

author = {Cogswell R and McGlothlin D and Kobashigawa E and Shaw R and De Marco T. },

year  = {2013},

date = {2013-03-03},

journal = {J Heart Lung Transplant},

volume = {32},

number = {293-8},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{,

title = {Multilayered regulation of cardiac ion channels},

author = {Zhang SS and Shaw RM},

year  = {2013},

date = {2013-03-03},

journal = {Biochim Biophys Acta},

volume = {1833},

number = {876-85},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23266405,

title = {Reduced sodium channels in human ARVC},

author = {Shaw RM},

year  = {2013},

date = {2013-03-01},

journal = {Heart Rhythm},

volume = {10},

number = {3},

pages = {420--421},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23596510,

title = {Dynasore protects mitochondria and improves cardiac lusitropy in Langendorff perfused mouse heart},

author = {Gao D, Zhang L, Dhillon R, Hong TT, Shaw RM, Zhu J},

year  = {2013},

date = {2013-01-01},

journal = {PLoS ONE},

volume = {8},

number = {4},

pages = {e60967},

abstract = {Heart failure due to diastolic dysfunction exacts a major economic, morbidity and mortality burden in the United States. Therapeutic agents to improve diastolic dysfunction are limited. It was recently found that Dynamin related protein 1 (Drp1) mediates mitochondrial fission during ischemia/reperfusion (I/R) injury, whereas inhibition of Drp1 decreases myocardial infarct size. We hypothesized that Dynasore, a small noncompetitive dynamin GTPase inhibitor, could have beneficial effects on cardiac physiology during I/R injury. In Langendorff perfused mouse hearts subjected to I/R (30 minutes of global ischemia followed by 1 hour of reperfusion), pretreatment with 1 µM Dynasore prevented I/R induced elevation of left ventricular end diastolic pressure (LVEDP), indicating a significant and specific lusitropic effect. Dynasore also decreased cardiac troponin I efflux during reperfusion and reduced infarct size. In cultured adult mouse cardiomyocytes subjected to oxidative stress, Dynasore increased cardiomyocyte survival and viability identified by trypan blue exclusion assay and reduced cellular Adenosine triphosphate(ATP) depletion. Moreover, in cultured cells, Dynasore pretreatment protected mitochondrial fragmentation induced by oxidative stress. Dynasore protects cardiac lusitropy and limits cell damage through a mechanism that maintains mitochondrial morphology and intracellular ATP in stressed cells. Mitochondrial protection through an agent such as Dynasore can have clinical benefit by positively influencing the energetics of diastolic dysfunction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid22300662,

title = {Plasma BIN1 correlates with heart failure and predicts arrhythmia in patients with arrhythmogenic right ventricular cardiomyopathy},

author = {Hong TT, Cogswell R, James CA, Kang G, Pullinger CR, Malloy MJ, Kane JP, Wojciak J, Calkins H, Scheinman MM, Tseng ZH, Ganz P, DeMarco T, Judge DP, and Shaw RM},

year  = {2012},

date = {2012-06-01},

journal = {Heart Rhythm},

volume = {9},

number = {6},

pages = {961--967},

abstract = {Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder involving diseased cardiac muscle. Bridging integrator 1 (BIN1) is a membrane-associated protein important to cardiomyocyte homeostasis and is downregulated in cardiomyopathy. We hypothesized that BIN1 could be released into the circulation and that blood-available BIN1 can provide useful data on the cardiac status of patients whose hearts are failing secondary to ARVC. To determine whether plasma BIN1 levels can be used to measure disease severity in patients with ARVC. We performed a retrospective cohort study of 24 patients with ARVC. Plasma BIN1 levels were assessed for their ability to correlate with cardiac functional status and predict ventricular arrhythmias. Mean plasma BIN1 levels were decreased in patients with ARVC with heart failure (15 ± 7 vs 60 ± 17 in patients without heart failure, P <.05; the plasma BIN1 level was 60 ± 10 in non-ARVC normal controls). BIN1 levels correlated inversely with number of previous ventricular arrhythmia (R = -.47; P <.05), and low BIN1 levels correctly classified patients with advanced heart failure or ventricular arrhythmia (receiver operator curve area under the curve of 0.88 ± 0.07). Low BIN1 levels also predicted future ventricular arrhythmias (receiver operator curve area under the curve of 0.89 ± 0.09). In a stratified analysis, BIN1 levels could predict future arrhythmias in patients without severe heart failure (n = 20) with an accuracy of 82%. In the 7 patients with ARVC with serial blood samples, all of whom had evidence of disease progression during follow-up, plasma BIN1 levels decreased significantly (a decrease of 63%; P <.05). Plasma BIN1 level seems to correlate with cardiac functional status and the presence or absence of sustained ventricular arrhythmias in a small cohort of patients with ARVC and can predict future ventricular arrhythmias.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}