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A nonsynonymous polymorphism in semaphorin 3A as a risk factor for human unexplained cardiac arrest with documented ventricular fibrillation.

ABSTRACT: Unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) is a major cause of sudden cardiac death. Abnormal sympathetic innervations have been shown to be a trigger of ventricular fibrillation. Further, adequate expression of SEMA3A was reported to be critical for normal patterning of cardiac sympathetic innervation. We investigated the relevance of the semaphorin 3A (SEMA3A) gene located at chromosome 5 in the etiology of UCA. Eighty-three Japanese patients diagnosed with UCA and 2,958 healthy controls from two different geographic regions in Japan were enrolled. A nonsynonymous polymorphism (I334V, rs138694505A>G) in exon 10 of the SEMA3A gene identified through resequencing was significantly associated with UCA (combined P?=?0.0004, OR 3.08, 95%CI 1.67-5.7). Overall, 15.7% of UCA patients carried the risk genotype G, whereas only 5.6% did in controls. In patients with SEMA3A(I334V), VF predominantly occurred at rest during the night. They showed sinus bradycardia, and their RR intervals on the 12-lead electrocardiography tended to be longer than those in patients without SEMA3A(I334V) (1031±111 ms versus 932±182 ms, P?=?0.039). Immunofluorescence staining of cardiac biopsy specimens revealed that sympathetic nerves, which are absent in the subendocardial layer in normal hearts, extended to the subendocardial layer only in patients with SEMA3A(I334V). Functional analyses revealed that the axon-repelling and axon-collapsing activities of mutant SEMA3A(I334V) genes were significantly weaker than those of wild-type SEMA3A genes. A high incidence of SEMA3A(I334V) in UCA patients and inappropriate innervation patterning in their hearts implicate involvement of the SEMA3A gene in the pathogenesis of UCA.

SUBMITTER: Nakano Y

PROVIDER: S-EPMC3623806 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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A nonsynonymous polymorphism in semaphorin 3A as a risk factor for human unexplained cardiac arrest with documented ventricular fibrillation.

Nakano Yukiko Y Chayama Kazuaki K Ochi Hidenori H Toshishige Masaaki M Hayashida Yasufumi Y Miki Daiki D Hayes C Nelson CN Suzuki Hidekazu H Tokuyama Takehito T Oda Noboru N Suenari Kazuyoshi K Uchimura-Makita Yuko Y Kajihara Kenta K Sairaku Akinori A Motoda Chikaaki C Fujiwara Mai M Watanabe Yoshikazu Y Yoshida Yukihiko Y Ohkubo Kimie K Watanabe Ichiro I Nogami Akihiko A Hasegawa Kanae K Watanabe Hiroshi H Endo Naoto N Aiba Takeshi T Shimizu Wataru W Ohno Seiko S Horie Minoru M Arihiro Koji K Tashiro Satoshi S Makita Naomasa N Kihara Yasuki Y

PLoS genetics 20130411 4

Unexplained cardiac arrest (UCA) with documented ventricular fibrillation (VF) is a major cause of sudden cardiac death. Abnormal sympathetic innervations have been shown to be a trigger of ventricular fibrillation. Further, adequate expression of SEMA3A was reported to be critical for normal patterning of cardiac sympathetic innervation. We investigated the relevance of the semaphorin 3A (SEMA3A) gene located at chromosome 5 in the etiology of UCA. Eighty-three Japanese patients diagnosed with ...[more]

PMID: 23593010

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Project description:IntroductionBesides therapeutic hypothermia or targeted temperature management no novel therapies have been developed to improve outcomes of patients after cardiac arrest (CA). Recent studies suggest that nitrite reduces neurological damage after asphyxial CA. Nitrite is also implicated as a new mediator of remote post conditioning produced by tourniquet inflation-deflation, which is under active investigation in CA. However, little is known about brain penetration or pharmacokinetics (PK). Therefore, to define the optimal use of this agent, studies on the PK of nitrite in experimental ventricular fibrillation (VF) are needed. We tested the hypothesis that nitrite administered after resuscitation from VF is detectable in cerebrospinal fluid (CSF), brain and other organ tissues, produces no adverse hemodynamic effects, and improves neurologic outcome in rats.MethodsAfter return of spontaneous circulation (ROSC) of 5 min untreated VF, adult male Sprague-Dawley rats were given intravenous nitrite (8 μM, 0.13 mg/kg) or placebo as a 5 min infusion beginning at 5 min after CA. Additionally, sham groups with and without nitrite treatment were also studied. Whole blood nitrite levels were serially measured. After 15 min, CSF, brain, heart and liver tissue were collected. In a second series, using a randomized and blinded treatment protocol, rats were treated with nitrite or placebo after arrest. Neurological deficit scoring (NDS) was performed daily and eight days after resuscitation, fear conditioning testing (FCT) and brain histology were assessed.ResultsIn an initial series of experiments, rats (n = 21) were randomized to 4 groups: VF-CPR and nitrite therapy (n = 6), VF-CPR and placebo therapy (n = 5), sham (n = 5), or sham plus nitrite therapy (n = 5). Whole blood nitrite levels increased during drug infusion to 57.14 ± 10.82 μM at 11 min post-resuscitation time (1 min after dose completion) in the VF nitrite group vs. 0.94 ± 0.58 μM in the VF placebo group (p < 0.001). There was a significant difference between the treatment and placebo groups in nitrite levels in blood between 7.5 and 15 min after CPR start and between groups with respect to nitrite levels in CSF, brain, heart and liver. In a second series (n = 25 including 5 shams), 19 out of 20 animals survived until day 8. However, NDS, FCT and brain histology did not show any statistically significant difference between groups.ConclusionsNitrite, administered early after ROSC from VF, was shown to cross the blood brain barrier after a 5 min VF cardiac arrest. We characterized the PK of intravenous nitrite administration after VF and were able to demonstrate nitrite safety in this feasibility study.

Project description:BACKGROUND:Quantitative measures of the ventricular fibrillation (VF) ECG waveform can assess myocardial physiology and predict cardiac arrest outcomes, making these measures a candidate to help guide resuscitation. Chest compressions are typically paused for waveform measure calculation because compressions cause ECG artifact. However, such pauses contradict resuscitation guideline recommendations to minimize cardiopulmonary resuscitation interruptions. We evaluated a comprehensive group of VF measures with and without ongoing compressions to determine their performance under both conditions for predicting functionally-intact survival, the study's primary outcome. METHODS:Five-second VF ECG segments were collected with and without chest compressions before 2755 defibrillation shocks from 1151 out-of-hospital cardiac arrest patients. Twenty-four individual measures and 3 combination measures were implemented. Measures were optimized to predict functionally-intact survival (Cerebral Performance Category score ?2) using 460 training cases, and their performance evaluated using 691 independent test cases. RESULTS:Measures predicted functionally-intact survival on test data with an area under the receiver operating characteristic curve ranging from 0.56 to 0.75 (median, 0.73) without chest compressions and from 0.53 to 0.75 (median, 0.69) with compressions ( P<0.001 for difference). Of all measures evaluated, the support vector machine model ranked highest both without chest compressions (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.73-0.78) and with compressions (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.72-0.78; P=0.75 for difference). CONCLUSIONS:VF waveform measures predict functionally-intact survival when calculated during chest compressions, but prognostic performance is generally reduced compared with compression-free analysis. However, support vector machine models exhibited similar performance with and without compressions while also achieving the highest area under the receiver operating characteristic curve. Such machine learning models may, therefore, offer means to guide resuscitation during uninterrupted cardiopulmonary resuscitation.

Dataset Information

A nonsynonymous polymorphism in semaphorin 3A as a risk factor for human unexplained cardiac arrest with documented ventricular fibrillation.

Publications

A nonsynonymous polymorphism in semaphorin 3A as a risk factor for human unexplained cardiac arrest with documented ventricular fibrillation.

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