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  • Ovid Technologies (Wolters Kluwer Health)  (12)
  • 1
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    Validated Risk Score for Predicting 6‐Month Mortality in Infective Endocarditis
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Journal of the American Heart Association Vol. 5, No. 4 ( 2016-04-03)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 5, No. 4 ( 2016-04-03)
    Abstract: Host factors and complications have been associated with higher mortality in infective endocarditis ( IE ). We sought to develop and validate a model of clinical characteristics to predict 6‐month mortality in IE . Methods and Results Using a large multinational prospective registry of definite IE (International Collaboration on Endocarditis [ ICE ]–Prospective Cohort Study [ PCS ], 2000–2006, n=4049), a model to predict 6‐month survival was developed by Cox proportional hazards modeling with inverse probability weighting for surgery treatment and was internally validated by the bootstrapping method. This model was externally validated in an independent prospective registry ( ICE ‐ PLUS , 2008–2012, n=1197). The 6‐month mortality was 971 of 4049 (24.0%) in the ICE ‐ PCS cohort and 342 of 1197 (28.6%) in the ICE ‐ PLUS cohort. Surgery during the index hospitalization was performed in 48.1% and 54.0% of the cohorts, respectively. In the derivation model, variables related to host factors (age, dialysis), IE characteristics (prosthetic or nosocomial IE , causative organism, left‐sided valve vegetation), and IE complications (severe heart failure, stroke, paravalvular complication, and persistent bacteremia) were independently associated with 6‐month mortality, and surgery was associated with a lower risk of mortality (Harrell's C statistic 0.715). In the validation model, these variables had similar hazard ratios (Harrell's C statistic 0.682), with a similar, independent benefit of surgery (hazard ratio 0.74, 95% CI 0.62–0.89). A simplified risk model was developed by weight adjustment of these variables. Conclusions Six‐month mortality after IE is ≈25% and is predicted by host factors, IE characteristics, and IE complications. Surgery during the index hospitalization is associated with lower mortality but is performed less frequently in the highest risk patients. A simplified risk model may be used to identify specific risk subgroups in IE .
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.115.003016
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 2653953-6
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  • 2
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    Online Resource
    Preconception Antidiabetic Drugs in Men and Birth Defects in Offspring: A Nationwide Cohort Study
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Obstetrical & Gynecological Survey Vol. 77, No. 7 ( 2022-7), p. 413-414
    Details
    In: Obstetrical & Gynecological Survey, Ovid Technologies (Wolters Kluwer Health), Vol. 77, No. 7 ( 2022-7), p. 413-414
    Abstract: (Abstracted from Ann Intern Med 2022;175:665–673) Diabetes mellitus is known to compromise sperm quality and is associated with impaired male fertility. Metformin is a first-line oral diabetes medication that has been shown to improve markers of semen quality in obese men but reduces serum testosterone levels independently of glycemic control.
    Type of Medium: Online Resource
    ISSN: 1533-9866 , 0029-7828
    URL: Article
    DOI: 10.1097/01.ogx.0000852732.84663.43
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2043471-6
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  • 3
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    Abstract 1254: Novel Insights In Arrhytmogenesis Of Catecholaminergic Ventricular Tachycardia From The First Knock In Model Of Homozygous Calsequestrin Mutation
    Ovid Technologies (Wolters Kluwer Health) ; 2007
    In:  Circulation Vol. 116, No. suppl_16 ( 2007-10-16)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 116, No. suppl_16 ( 2007-10-16)
    Abstract: Cardiac Calsequestrin (CASQ2) is a high affinity low capacity calcium binding protein essential in the regulation of intracellular Ca storage and release. Mutations in CASQ2 have been linked to the recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVTr). To elucidate the mechanisms of arrhythmogensis in CPVTr, we generated a knock-in mouse model carrier of the R33Q mutation identified in one of our patients (pts) with a severe CPVT phenotype. Continuous ECG recording (DSI implantable monitors) showed that homozygous (CASQ2 R33Q/R33Q ) mice develop bidirectional and polymorphic VT upon exposure to adrenergic triggers (noise, physical contact). CASQ2 R33Q/R33Q mice have no sign of structural cardiac abnormality (normal heart/body weight ratio, histology no fibrosis nor myofibrillar disarray). Calcium-binding affinity of CASQ2 R33Q/R33Q is identical to that of wild type (WT) CASQ2, its localization evaluated with confocal microscopy is superimposable to that of WT. Western blot analysis shows that CASQ2 R33Q/R33Q content in myocytes is reduced by 40% but Real Time PCR showed that levels of mRNA are not reduced suggesting an abnormal protein turn-over. Evaluation of electrophysiological properties of isolated CASQ2 R33Q/R33Q myocytes revealed that pacing (1–5 Hz) induces delayed afterdepolarizations (DADs; 18/32 cells 56%) and triggered activity (TA; 9/31 29%) addition of adrenalin (200 nM) enhances DADs and TA (DADs 15/16 cells 93%; TA 8/17 cells 47%) and also elicits (25% of myocytes) early after depolarizations (EADs) and EADs-mediated TA. Our data demonstrate that in analogy with our knock-in model of the dominant form of CPVT due to mutations in the cardiac ryanodine receptor (RyR2) the CASQ2 R33Q/R33Q mice 1) do not present signs of cardiomyopathy, 2) develop DADs and TA in vitro and bidirectional and polymorphic VT in vivo. At variance with RyR2 mice, CASQ2 R33Q/R33Q mice 1) present a more malignant phenotype, lower threshold for DADs, TA and VT; 2) EADs concur to arrhythmogenesis 3) overcoming with a knock-in the limitations of previous in vitro and in vivo models overexpressing mutant CASQ2 on the background of the WT protein we demonstrated that a reduction in CASQ2 is implicated in the arrhythmogenesis of recessive CPVT.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.116.suppl_16.II_255-b
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2007
    detail.hit.zdb_id: 1466401-X
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  • 4
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    Clinical Phenotype and Functional Characterization of CASQ2 Mutations Associated With Catecholaminergic Polymorphic Ventricular Tachycardia
    Ovid Technologies (Wolters Kluwer Health) ; 2006
    In:  Circulation Vol. 114, No. 10 ( 2006-09-05), p. 1012-1019
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 114, No. 10 ( 2006-09-05), p. 1012-1019
    Abstract: Background— Four distinct mutations in the human cardiac calsequestrin gene ( CASQ2 ) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). The mechanisms leading to the clinical phenotype are still poorly understood because only 1 CASQ2 mutation has been characterized in vitro. Methods and Results— We identified a homozygous 16-bp deletion at position 339 to 354 leading to a frame shift and a stop codon after 5aa (CASQ2 G112+5X ) in a child with stress-induced ventricular tachycardia and cardiac arrest. The same deletion was also identified in association with a novel point mutation (CASQ2 L167H ) in a highly symptomatic CPVT child who is the first CPVT patient carrier of compound heterozygous CASQ2 mutations. We characterized in vitro the properties of CASQ2 mutants: CASQ2 G112+5X did not bind Ca 2+ , whereas CASQ2 L167H had normal calcium-binding properties. When expressed in rat myocytes, both mutants decreased the sarcoplasmic reticulum Ca 2+ -storing capacity and reduced the amplitude of I Ca -induced Ca 2+ transients and of spontaneous Ca 2+ sparks in permeabilized myocytes. Exposure of myocytes to isoproterenol caused the development of delayed afterdepolarizations in CASQ2 G112+5X . Conclusions— CASQ2 L167H and CASQ2 G112+5X alter CASQ2 function in cardiac myocytes, which leads to reduction of active sarcoplasmic reticulum Ca 2+ release and calcium content. In addition, CASQ2 G112+5X displays altered calcium-binding properties and leads to delayed afterdepolarizations. We conclude that the 2 CASQ2 mutations identified in CPVT create distinct abnormalities that lead to abnormal intracellular calcium regulation, thus facilitating the development of tachyarrhythmias.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.106.623793
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2006
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  • 5
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    Increased Ca 2+ Sensitivity of the Ryanodine Receptor Mutant RyR2 R4496C Underlies Catecholaminergic Polymorphic Ventricular Tachycardia
    Ovid Technologies (Wolters Kluwer Health) ; 2009
    In:  Circulation Research Vol. 104, No. 2 ( 2009-01-30), p. 201-209
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 104, No. 2 ( 2009-01-30), p. 201-209
    Abstract: Cardiac ryanodine receptor (RyR2) mutations are associated with autosomal dominant catecholaminergic polymorphic ventricular tachycardia, suggesting that alterations in Ca 2+ handling underlie this disease. Here we analyze the underlying Ca 2+ release defect that leads to arrhythmia in cardiomyocytes isolated from heterozygous knock-in mice carrying the RyR2 R4496C mutation. RyR2 R4496C−/− littermates (wild type) were used as controls. [Ca 2+ ] i transients were obtained by field stimulation in fluo-3–loaded cardiomyocytes and viewed using confocal microscopy. In our basal recording conditions (2-Hz stimulation rate), [Ca 2+ ] i transients and sarcoplasmic reticulum Ca 2+ load were similar in wild-type and RyR2 R4496C cells. However, paced RyR2 R4496C ventricular myocytes presented abnormal Ca 2+ release during the diastolic period, viewed as Ca 2+ waves, consistent with the occurrence of delayed afterdepolarizations. The occurrence of this abnormal Ca 2+ release was enhanced at faster stimulation rates and by β-adrenergic stimulation, which also induced triggered activity. Spontaneous Ca 2+ sparks were more frequent in RyR2 R4496C myocytes, indicating increased RyR2 R4496C activity. When permeabilized cells were exposed to different cytosolic [Ca 2+ ] i , RyR2 R4496C showed a dramatic increase in Ca 2+ sensitivity. Isoproterenol increased [Ca 2+ ] i transient amplitude and Ca 2+ spark frequency to the same extent in wild-type and RyR2 R4496C cells, indicating that the β-adrenergic sensitivity of RyR2 R4496C cells remained unaltered. This effect was independent of protein expression variations because no difference was found in the total or phosphorylated RyR2 expression levels. In conclusion, the arrhythmogenic potential of the RyR2 R4496C mutation is attributable to the increased Ca 2+ sensitivity of RyR2 R4496C , which induces diastolic Ca 2+ release and lowers the threshold for triggered activity.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.108.177493
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2009
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  • 6
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    Synergistic Impact of Systolic Blood Pressure and Perfusion Status on Mortality in Acute Heart Failure
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation: Heart Failure Vol. 14, No. 3 ( 2021-03)
    Details
    In: Circulation: Heart Failure, Ovid Technologies (Wolters Kluwer Health), Vol. 14, No. 3 ( 2021-03)
    Abstract: Physical examination remains the cornerstone in the assessment of acute heart failure. There is a lack of adequately powered studies assessing the combined impact of both systolic blood pressure (SBP) and hypoperfusion on short-term mortality. Methods: Patients with acute heart failure from 41 Spanish emergency departments were recruited consecutively in 3 time periods between 2011 and 2016. Logistic regression models were used to assess the association of 30-day mortality with SBP ( 〈 90, 90–109, 110–129, and ≥130 mm Hg) and with manifestations of hypoperfusion (cold skin, cutaneous pallor, delayed capillary refill, livedo reticularis, and mental confusion) at admission. Results: Among 10 979 patients, 1143 died within the first 30 days (10.2%). There was an inverse association between 30-day mortality and initial SBP (35.4%, 18.9%, 12.4%, and 7.5% for SBP 〈 90, SBP 90–109, SBP 110–129, and SBP≥130 mm Hg, respectively; P 〈 0.001) and a positive association with hypoperfusion (8.0%, 14.8%, and 27.6% for those with none, 1, ≥2 signs/symptoms of hypoperfusion, respectively; P 〈 0.001). After adjustment for 11 risk factors, the prognostic impact of hypoperfusion on 30-day mortality varied across SBP categories: SBP≥130 mm Hg (odds ratio [OR]=1.03 [95% CI, 0.77–1.36] and OR=1.18 [95% CI, 0.86–1.62] for 1 and ≥2 compared with 0 manifestations of hypoperfusion), SBP 110 to 129 mm Hg (OR=1.23 [95% CI, 0.86–1.77] and OR=2.18 [95% CI, 1.44–3.31], respectively), SBP 90 to 109 mm Hg (OR=1.29 [95% CI, 0.79–2.10] and OR=2.24 [95% CI, 1.36–3.66], respectively), and SBP 〈 90 mm Hg (OR=1.34 [95% CI, 0.45–4.01] and OR=3.22 [95% CI, 1.30–7.97] , respectively); P -for-interaction =0.043. Conclusions: Hypoperfusion confers an incremental risk of 30-day all-cause mortality not only in patients with low SBP but also in normotensive patients. On admission, physical examination plays a major role in determining prognosis in patients with acute heart failure.
    Type of Medium: Online Resource
    ISSN: 1941-3289 , 1941-3297
    URL: Article
    DOI: 10.1161/CIRCHEARTFAILURE.120.007347
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2428100-1
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  • 7
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    Arrhythmogenesis in Catecholaminergic Polymorphic Ventricular Tachycardia : Insights From a RyR2 R4496C Knock-In Mouse Model
    Ovid Technologies (Wolters Kluwer Health) ; 2006
    In:  Circulation Research Vol. 99, No. 3 ( 2006-08-04), p. 292-298
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 99, No. 3 ( 2006-08-04), p. 292-298
    Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by life threatening arrhythmias and mutations in the gene encoding the ryanodine receptor (RyR2). Disagreement exists on whether (1) RyR2 mutations induce abnormal calcium transients in the absence of adrenergic stimulation; (2) decreased affinity of mutant RyR2 for FKBP12.6 causes CPVT; (3) K201 prevent arrhythmias by normalizing the FKBP12.6-RyR2 binding. We studied ventricular myocytes isolated from wild-type (WT) and knock-in mice harboring the R4496C mutation (RyR2 R4496C+/− ). Pacing protocols did not elicit delayed afterdepolarizations (DADs) (n=20) in WT but induced DADs in 21 of 33 (63%) RyR2 R4496C+/− myocytes ( P =0.001). Superfusion with isoproterenol (30 nmol/L) induced small DADs (45%) and no triggered activity in WT myocytes, whereas it elicited DADs in 87% and triggered activity in 60% of RyR2 R4496C+/− myocytes ( P =0.001). DADs and triggered activity were abolished by ryanodine (10 μmol/L) but not by K201 (1 μmol/L or 10 μmol/L). In vivo administration of K201 failed to prevent induction of polymorphic ventricular tachycardia (VT) in RyR2 R4496C+/− mice. Measurement of the FKBP12.6/RyR2 ratio in the heavy sarcoplasmic reticulum membrane showed normal RyR2–FKBP12.6 interaction both in WT and RyR2 R4496C+/− either before and after treatment with caffeine and epinephrine. We suggest that (1) triggered activity is the likely arrhythmogenic mechanism of CPVT; (2) K201 fails to prevent DADs in RyR2 R4496C+/− myocytes and ventricular arrhythmias in RyR2 R4496C+/− mice; and (3) RyR2–FKBP12.6 interaction in RyR2 R4496C+/− is identical to that of WT both before and after epinephrine and caffeine, thus suggesting that it is unlikely that the R4496C mutation interferes with the RyR2/FKBP12.6 complex.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.0000235869.50747.e1
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2006
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  • 8
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    Abstract 3818: Notch1 Receptor Blockade Results in Dilated Cardiomyopathy in the Neonatal Mouse Heart
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Circulation Vol. 118, No. suppl_18 ( 2008-10-28)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 118, No. suppl_18 ( 2008-10-28)
    Abstract: The objective of this study was to determine whether Notch1 receptor plays a crucial role in the commitment of c-kit-positive cardiac progenitor cells (CPCs) to the myocyte lineage. This possibility was tested in the neonatal mouse heart because of the dramatic increase in the myocyte compartment early postnatally. CPCs are located within the primitive heart and their number increases progressively with gestational age and after birth. c-kit colocalizes with transcription factors and contractile proteins specific of myocytes, pointing to a lineage relationship between CPCs and myocytes in the prenatal and postnatal heart. Notch1 intracellular domain (N1ICD) was consistently found together with Nkx2.5 suggesting that Notch1 receptor represents an early determinant of myocyte differentiation. The critical function of Notch1 in the generation of myocytes was established by interfering with this pathway through the administration of a γ-secretase inhibitor to newborn mice for 3–7 days; γ-secretase inhibition opposes the cleavage of the active fragment of Notch and initiation of transcription. Treated mice showed a dilated myopathy characterized by decreased muscle mass, wall thinning and impaired fractional shortening and ejection fraction. There was also a marked reduction in the fraction of CPCs and myocytes expressing the Notch1 active fragment N1ICD. Myocyte number decreased 28% while myocyte volume remained constant, suggesting that Notch1 blockade affects myocyte formation and conditions the development of a dilated myopathy. This hypothesis is supported further by a 57% decrease in replicating myocytes positive for Ki67. These anatomical and functional changes were accompanied by downregulation of Nkx2.5 transcripts in the pathologic heart. A perfect consensus site for the target gene of Notch, RBP-Jk, was recognized in the promoter of Nkx2.5. The formation of a functional complex between Nkx2.5 promoter and RBP-Jk protein was demonstrated by electrophoretic mobility assay, chromatin immunoprecipitation and luciferase reporter assay. In conclusion, Notch1 promotes the commitment of CPCs to the myocyte lineage and inhibition of Notch1 interferes with cardiomyogenesis leading to a dilated cardiomyopathy in the postnatal heart.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.118.suppl_18.S_490-c
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
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  • 9
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    Endogenous nociceptin/orphanin FQ signalling produces opposite spinal antinociceptive and supraspinal pronociceptive effects in the mouse formalin test: Pharmacological and genetic evidences
    Ovid Technologies (Wolters Kluwer Health) ; 2006
    In:  Pain Vol. 124, No. 1 ( 2006-09), p. 100-108
    Details
    In: Pain, Ovid Technologies (Wolters Kluwer Health), Vol. 124, No. 1 ( 2006-09), p. 100-108
    Type of Medium: Online Resource
    ISSN: 0304-3959
    URL: Article
    DOI: 10.1016/j.pain.2006.03.021
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2006
    detail.hit.zdb_id: 1494115-6
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  • 10
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    Abstract 2257: KCNJ2 Mutations in Patients Referred for Catecholaminergic Polymorphic Ventricular Tachycardia Gene Screening
    Ovid Technologies (Wolters Kluwer Health) ; 2007
    In:  Circulation Vol. 116, No. suppl_16 ( 2007-10-16)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 116, No. suppl_16 ( 2007-10-16)
    Abstract: Background : Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by adrenergically mediated polymorphic or bidirectional ventricular tachycardia (BVT). Andersen-Tawil syndrome (ATS1), which are mainly caused by KCNJ2 mutations, phenocopies CPVT and may manifest the typical adrenergically mediated BVT. The purpose of this study was assess whether patients (pts) lacking periodic paralysis typical of ATS1 and diagnosed as CPVT because of BVT carry KCNJ2 mutations. Methods and Results : Mutational analysis of KCNJ2 was performed in 23 RyR2 and CASQ2 genotype-negative CPVT pts with normal QT interval. Two novel missense mutations (S220I and T305I) were identified. Mutations were absent in 〉 400 reference alleles. Both of the pts present exercise or isoproterenol induced BVT, baseline ECG with prominent U wave and mild facial abnormalities. In vitro characterization showed that no current is detectable when S220I and T305I mutants clones are expressed; on the contrary co-expression of WT and mutant KCNJ2 to mimic heterozygosis present in patients, caused significant dominant negative effect (see figure ). Confocal laser microscopy revealed normal sarcolemmal localization of the mutant channels and of the heterozygous channels. Conclusions : KCNJ2 mutation with loss of function are present in a minority of pts with clinical diagnosis of CPVT. Given the limited number of CPVT pts with KCNJ2 mutations it is impossible to determine whether their prognosis is identical to that of RyR2 and CASQ2 related CPVT. Screening of KCNJ2 should be considered in CPVT pts without mutations in RyR2 and CASQ2 genes.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.116.suppl_16.II_492
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2007
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