Sema3a maintains normal heart rhythm through sympathetic innervation patterning

Ieda, Masaki; Kanazawa, Hideaki; Kimura, Kensuke; Hattori, Fumiyuki; Ieda, Yasuyo; Taniguchi, Masahiko; Lee, Jong Kook; Matsumura, Keisuke; Tomita, Yuichi; Miyoshi, Shunichiro; Shimoda, Kouji; Makino, Shinji; Sano, Motoaki; Kodama, Itsuo; Ogawa, Satoshi; Fukuda, Keiichi

doi:10.1038/nm1570

Cited by 207 publications

(225 citation statements)

References 42 publications

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“…Those results or ours suggest that SNS abnormality is more sensitive for predicting arrhythmic events than is left ventricular dysfunction or structural heart disease. Our results may support the possibility that SNS activity contributes to the fine control of cardiac performance on demand, but not cardiac function (30).…”

Section: Sns Abnormality In Patients With a History Of Ventricular Arsupporting

confidence: 72%

“…Those results support the close relationship between left ventricular function and SNS activity in patients with ventricular tachyarrhythmia. On the other hand, patients who underwent heart transplantation and had denervated hearts did not show severe left ventricular dysfunction, but about 10% of the patients experienced sudden cardiac death, presumably due to arrhythmia (29), suggesting a direct effect of SNS abnormality (30)(31)(32). In the present study, SNS abnormality increased the occurrence of recurrent ventricular arrhythmia independent of left ventricular dysfunction or structural heart disease.…”

Section: Sns Abnormality In Patients With a History Of Ventricular Arcontrasting

confidence: 41%

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The Significance of Cardiac Sympathetic Nervous System Abnormality in the Long-Term Prognosis of Patients with a History of Ventricular Tachyarrhythmia

Akutsu¹,

Kaneko²,

Kodama³

et al. 2008

J Nucl Med

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Severe left ventricular dysfunction or cardiac sympathetic nervous system (SNS) abnormality predicts cardiac death in various heart diseases, including arrhythmogenic disorders. However, it is not clear whether SNS abnormality predicts sudden cardiac death during long-term follow-up in patients with a history of ventricular tachyarrhythmia. We hypothesized that SNS abnormality would be associated with recurrent ventricular arrhythmic events. Methods: 123 I-metaiodobenzylguanidine (MIBG) scintigraphy was performed on 86 patients (mean age 6 SD, 46 6 19 y, 65.1% men) with a history of ventricular tachycardia or fibrillation. 123 I-MIBG (111 MBq) was intravenously administered under resting conditions, and planar images were obtained 15 min and 4 h later (anterior view for 6 min; 512 · 512 matrices; zoom ratio, 1.0). SNS activity was assessed using the heart-to-mediastinum ratio on delayed imaging. Results: During about 11 y of followup (mean 6 SD, 5.2 6 3.7 y), 3 patients (3.5%) had sudden cardiac death and 21 patients (24.4%) had sustained ventricular tachyarrhythmic events. SNS abnormality, defined as a heart-tomediastinum ratio of less than 2.8, and left ventricular dysfunction, defined as a left ventricular ejection fraction of less than 50%, were associated with sudden cardiac death or recurrent ventricular tachyarrhythmic events (18/40 patients [45%] with SNS abnormality, vs. 6/46 patients [13%] without, P 5 0.004; 9/15 patients [60%] with left ventricular dysfunction, vs. 15/71 patients [21.1%] without, P 5 0.008). After adjustment for potential confounding variables such as age, sex, coronary risk factors, medication use, history of structural heart disease, and left ventricular function, SNS abnormality was a powerful predictor of recurrent arrhythmic events, with a hazard ratio of 3.6 [95% confidence interval, 1.4-9.2, P 5 0.007]). Further, SNS abnormality had incremental and additive prognostic power in combination with left ventricular dysfunction, with an adjusted hazard ratio of 4.4 [95% confidence interval, 1.9-9.9, P , 0.0001]). Conclusion: SNS abnormality predicted recurrent ventricular tachyarrhythmic events during long-term follow-up. 123 I-MIBG scintigraphic evaluations for SNS abnormality may be an option for screening patients at high risk for sudden cardiac death.

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Section: Sns Abnormality In Patients With a History Of Ventricular Arsupporting

confidence: 72%

Section: Sns Abnormality In Patients With a History Of Ventricular Arcontrasting

confidence: 41%

The Significance of Cardiac Sympathetic Nervous System Abnormality in the Long-Term Prognosis of Patients with a History of Ventricular Tachyarrhythmia

Akutsu¹,

Kaneko²,

Kodama³

et al. 2008

J Nucl Med

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“…Sema3a has been identified as the chemorepellent agent inducing growth cone collapse and repelling sympathetic axons in the heart, as opponent of NGF, reported to be required for active sympathetic axon growth and innervation in the heart [Ieda et al, 2004[Ieda et al, , 2007Kuruvilla et al, 2004]. It could be shown that mice targeted with Sema3a or those overexpressing the gene display sudden cardiac death or lethal arrhythmias due to disruption of innervation patterning.…”

Section: Discussionmentioning

confidence: 99%

“…Apart from its role within the central neuronal system, SEMA3A is also important for development and plasticity of the peripheral system contributing to cardiac sympathetic innervation, and T-cell migration [Ieda et al, 2004[Ieda et al, , 2007Garcia et al, 2011]. SEMA3A is also distinctively and differentially expressed in spinal cord motor neurons and its signaling controls the timing of motor axon ingrowth to the limb [Cohen et al, 2005;Huber et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

Biallelic SEMA3A defects cause a novel type of syndromic short stature

Hofmann

Zweier

Sticht

et al. 2013

American J of Med Genetics Pt A

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Chromosomal microarray testing is commonly used to identify disease causing de novo copy number variants in patients with developmental delay and multiple congenital anomalies. In such a patient we now observed an 150 kb deletion on chromosome 7q21.11 affecting the first exon of the axon guidance molecule gene SEMA3A (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A). This deletion was inherited from the healthy father, but considering the function of SEMA3A and phenotypic similarity to the knock‐out mice, we still assumed a pathogenic relevance and tested for a recessive second defect. Sequencing of SEMA3A in the patient indeed revealed the de novo in‐frame mutation p.Phe316_Lys317delinsThrSerSerAsnGlu. Cloning of the mutated allele in combination with two informative SNPs confirmed compound heterozygosity in the patient. While the altered protein structure was predicted to be benign, aberrant splicing resulting in a premature stop codon was proven by RT‐PCR to occur in about half of the transcripts from this allele. Expression profiling in human fetal and adult cDNA panels, confirmed a high expression of SEMA3A in all brain regions as well as in adult and fetal heart and fetal skeletal muscle. Normal intellectual development in the patient was surprising but may be explained by the remaining 20% of SEMA3A expression level demonstrated by quantitative RT‐PCR. We therefore report a novel autosomal recessive syndrome characterized by postnatal short stature with relative macrocephaly, camptodactyly, septal heart defect and several minor anomalies caused by biallelic mutations in SEMA3A. © 2013 Wiley Periodicals, Inc.

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“…The response of the heart to sympathetic stimulation is modulated by the protein Semaphorin 3a (54). Semaphorin 3a-transgenic mice show catecholamine suprasensitivity and prolonged QT; they die from sudden death.…”

Section: Autonomic Nerve Dysfunction and Sympathetic Overactivitymentioning

confidence: 99%

The Challenge of Sudden Death in Dialysis Patients

Ritz¹,

Wanner²

2008

Clinical Journal of the American Society of Nephrology

114

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A 60-yr-old patient with ESRD (82 kg/168 cm), hypertension for the previous 18 yr, and type 2 diabetes is found dead in bed by his wife at home on a Saturday morning. The patient's history is notable for having started dialysis 34 weeks previously. His last dialysis had been the previous day (on a Friday afternoon). Predialysis potassium had been 5.7 mmol/L, the dialysate K ϩ was 2.0 mmol/L, and Mg 2ϩ was 0.5 mmol/L. Autopsy was not performed.Before his morbid event, the patient had been doing well on dialysis. He had less than 6 episodes of hypotension (Ͻ100 mmHg) per month. His average predialytic weight gain was 4 kg, and, with fluctuations, his average predialysis BP was 155/65 mmHg. While continuing on gliquidone (an oral sulfonylurea hypoglycemic drug that does not accumulate in renal failure), he had no episodes of hypoglycemia, and his last glycosylated hemoglobin level was 7.2%. His medical history is of hypertension, type 2 diabetes, and left ventricular hypertrophy (LVH) with an ejection fraction of 55%. His electrocardiogram showed signs of LVH and flat T waves. He had no history of hypoglycemic episodes and no evidence of retinopathy. He reported no episodes of arrhythmia or precordial pain. A predialysis chest x-ray 2 wk before the terminal event had shown pulmonary congestion. His medications included 0.25 g/d calcitriol, calcium carbonate, 10 mg of folate, 80 mg of verapamil, and no ␤ blockers. In addition, he received varying doses of darbepoietin and iron gluconate as required. He did not receive a statin. Dr. Eberhard Ritz: This case, unfortunately, is the usual presentation of patients on dialysis who succumb to sudden death: There are few, if any, specific premonitory symptoms or signs, cardiac standstill is usually the presenting symptom, and autopsy is not performed, so more specific information on underlying cardiac pathology, if any, is not available. The lack of pathoanatomic confirmation of the underlying pathology or pathologies-as in this case-continues to remain a problem that in the future should come onto the radar screen of nephrologists.Nevertheless, this case presentation raises a number of unresolved issues and provides an occasion to discuss how the currently unsatisfactory results might be improved in the future. In this context, it is of interest to have a look at the recent 4D study.

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Sema3a maintains normal heart rhythm through sympathetic innervation patterning

Cited by 207 publications

References 42 publications

The Significance of Cardiac Sympathetic Nervous System Abnormality in the Long-Term Prognosis of Patients with a History of Ventricular Tachyarrhythmia

The Significance of Cardiac Sympathetic Nervous System Abnormality in the Long-Term Prognosis of Patients with a History of Ventricular Tachyarrhythmia

Biallelic SEMA3A defects cause a novel type of syndromic short stature

The Challenge of Sudden Death in Dialysis Patients

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