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Articles by G Kang
Total Records ( 3 ) for G Kang
  G Kang , S. F Giovannone , N Liu , F. Y Liu , J Zhang , S. G Priori and G. I. Fishman
  Rationale:

The Purkinje fiber network has been proposed as the source of arrhythmogenic Ca2+ release events in catecholaminergic polymorphic ventricular tachycardia (CPVT), yet evidence supporting this mechanism at the cellular level is lacking.

Objective:

We sought to determine the frequency and severity of spontaneous Ca2+ release events and the response to the antiarrhythmic agent flecainide in Purkinje cells and ventricular myocytes from RyR2R4496C/+ CPVT mutant mice and littermate controls.

Methods and Results:

We crossed RyR2R4496C/+ knock-in mice with the newly described Cntn2-EGFP BAC transgenic mice, which express a fluorescent reporter gene in cells of the cardiac conduction system, including the distal Purkinje fiber network. Isolated ventricular myocytes (EGFP) and Purkinje cells (EGFP+) from wild-type hearts and mutant hearts were distinguished by epifluorescence and intracellular Ca2+ dynamics recorded by microfluorimetry. Both wild-type and RyR2R4496C/+ mutant Purkinje cells displayed significantly slower kinetics of activation and relaxation compared to ventricular myocytes of the same genotype, and decay in the mutant Purkinje cells was significantly slower than that observed in wild-type Purkinje cells. Of the 4 groups studied, RyR2R4496C/+ mutant Purkinje cells were also most likely to develop spontaneous Ca2+ release events, and the number of events per cell was also significantly greater. Furthermore, with isoproterenol treatment, although all 4 groups showed increases in the frequency of arrhythmogenic Ca2+i events, the RyR2R4496C/+ Purkinje cells responded with the most profound abnormalities in intracellular Ca2+ handling, including a significant increase in the frequency of unstimulated Ca2+i events and the development of alternans, as well as isolated and sustained runs of triggered beats. Both Purkinje cells and ventricular myocytes from wild-type mice showed suppression of spontaneous Ca2+ release events with flecainide, whereas in RyR2R4496C/+ mice, the Purkinje cells were preferentially responsive to drug. In contrast, the RyR2 blocker tetracaine was equally efficacious in mutant Purkinje cells and ventricular myocytes.

Conclusions:

Purkinje cells display a greater propensity to develop abnormalities in intracellular Ca2+ handling than ventricular myocytes. This proarrhythmic behavior is enhanced by disease-causing mutations in the RyR2 Ca2+ release channel and greatly exacerbated by catecholaminergic stimulation, with the development of arrhythmogenic triggered beats. These data support the concept that Purkinje cells are critical contributors to arrhythmic triggers in animal models and humans with CPVT and suggest a broader role for the Purkinje fiber network in the genesis of ventricular arrhythmias.

  B. A Pallante , S Giovannone , L Fang Yu , J Zhang , N Liu , G Kang , W Dun , P. A Boyden and G. I. Fishman
 

Background— Purkinje cells (PCs) comprise the most distal component of the cardiac conduction system, and their unique electrophysiological properties and the anatomic complexity of the Purkinje fiber network may account for the prominent role these cells play in the genesis of various arrhythmic syndromes.

Methods and Results— Differential transcriptional profiling of murine Purkinje fibers and working ventricular myocytes was performed to identify novel genes expressed in PCs. The most highly enriched transcript in Purkinje fibers encoded Contactin-2 (Cntn2), a cell adhesion molecule critical for neuronal patterning and ion channel clustering. Endogenous expression of Cntn2 in the murine ventricle was restricted to a subendocardial network of myocytes that also express β-galactosidase in CCS-lacZ transgenic mice and the connexin40 gap junction protein. Both Cntn2-lacZ knockin mice and Cntn2-EGFP BAC transgenic reporter mice confirmed expression of Cntn2 in the Purkinje fiber network, as did immunohistochemical staining of single canine Purkinje fibers. Whole-cell patch-clamp recordings and measurements of Ca2+ transients in Cntn2-EGFP+ cells revealed electrophysiological properties indicative of PCs and distinctive from those of cardiac myocytes, including prolonged action potentials and frequent afterdepolarizations.

Conclusions— Cntn2 is a novel marker of the specialized cardiac conduction system. Endogenous expression of Cntn2 as well as Cntn2-dependent transcriptional reporters provides a new tool through which Purkinje cell biology and pathophysiology can now more readily be deciphered. Expression of a contactin family member within the CCS may provide a mechanistic basis for patterning of the conduction system network and the organization of ion channels within Purkinje cells.

  B. P Gladstone , A. R Das , A. M Rehman , S Jaffar , M. K Estes , J Muliyil , G Kang and A. Bose
 

The morbidity and mortality in a cohort of 452 children followed up from birth up to 3 years of age, in an urban slum in India, is described. These children were recruited and followed from March 2002 to September 2006. A prospective morbidity survey was established. There were 1162 child-years of follow-up. The average morbidity rate was 11.26 episodes/child-year. Respiratory infections caused 58.3 and diarrheal disease 18.4% of the illnesses. Respiratory illnesses resulted in 48, 67.5 and 50 days of illnesses, and there were 3.6, 1.64 and 1.16 diarrheal episodes per child in the 3 years, respectively. There were five deaths in the cohort in the 3 years of follow-up. Of the 77 drop-outs 44 were contacted for mortality data. The morbidity in the area is high, comparable to other studies. The mortality is low, and is attributed to the facilitated access to care.

 
 
 
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