An inherited sudden cardiac arrest syndrome may be based on primary myocardial and autonomic nervous system abnormalities.

BACKGROUND: A recently discovered sudden cardiac arrest (SCA) syndrome is linked to a risk haplotype that harbors the dipeptidyl-peptidase 6 (DPP6) gene as a plausible culprit. OBJECTIVE: Because DPP6 impacts both cardiomyocyte and neuronal function, we hypothesized that ventricular fibrillation (VF) in risk haplotype carriers arises from functional changes in both the heart and autonomic nervous system. METHODS: We studied 6 risk haplotype carriers with previous VF (symptomatic), 8 carriers without VF (asymptomatic), and 7 noncarriers (controls). We analyzed supine and standing heart rate variability, baroreflex sensitivity, pre-VF heart rate changes, and myocardial 123I-meta-iodobenzylguanide (123I-mIBG) scintigraphy. RESULTS: Carriers had longer interbeat intervals than controls (1.03 ± 0.11 seconds vs 0.81 ± 0.07 seconds; P <.001), lower low-frequency (LF) and higher high-frequency (HF) activity, and lower LF/HF ratio (0.68 ± 0.50 vs 2.11 ± 1.10; P = .013) in the supine position. Upon standing up, carriers had significantly larger decrease in interbeat interval and increase in LF than controls (standing-to-supine ratio: 0.78 ± 0.07 vs 0.90 ± 0.07; P = .002; and 1.94 ± 1.03 vs 1.17 ± 0.34; P = .022, respectively), and nonsignificantly larger decrease in HF (0.62 ± 0.36 vs 0.97 ± 0.42; P = .065) and increase in LF/HF ratio (5.55 ± 6.79 vs 1.62 ± 1.24; P = .054). Sixteen of 17 VF episodes occurred at rest. Heart rate immediately before VF was 110 ± 25 bpm. Symptomatic carriers had less heterogeneous 123I-mIBG distribution in the left ventricle than asymptomatic carriers (single-photon emission computed tomography score ≥3 in 7 asymptomatic and 1 symptomatic carrier; P = .008). CONCLUSION: It can be speculated that these data are consistent with more labile autonomic tone in carriers, suggesting that the primary abnormalities may reside in both the heart and the autonomic nervous system.

Report of Autonomic Symptoms in a Clinical Sample of Veterans with Gulf War Illness.

Introduction: Previous studies suggest that autonomic dysfunction may be an underlying factor in Gulf War Illness. This study examined self-reported symptoms of autonomic dysfunction and their relationship with physical functioning among veterans with Gulf War Illness. Materials and Methods: We abstracted medical records of Gulf War Veterans clinically evaluated at the New Jersey War Related Illness and Injury Study Center between 2010 and 2016. The outcome measure was the Veteran version of the Short Form Health Survey (VR-36) physical functioning scale. Autonomic function was assessed using a composite variable constructed from the chart abstraction to mimic the Composite Autonomic Symptom Scale (COMPASS-31). Results: Seventy-six veterans were included in the final analysis. The autonomic symptom burden score was 45 (±14). Increased autonomic symptom burden, greater mental health burden (PTSD/depression), and greater body mass index were individually associated with poorer physical functioning. A general linear regression containing these variables revealed that patients with both PTSD and depression (b = -15.2, p = 0.03) or either PTSD or depression (b = -22.7, p < 0.01) had lower physical functioning than those without; the other variables became not significant (body mass index: p = 0.07; autonomic function: p = 0.89). Conclusion: The average autonomic function score indicated significant burden in Gulf War Veterans, consistent with published research. We did not detect an independent association between autonomic symptom burden and physical functioning, likely due to the non-specific nature of the measure used to capture autonomic symptoms or the stronger association between mental health conditions and physical functioning. Future work utilizing valid and standardized instruments to clinically evaluate autonomic function is warranted.

Sinais e sintomas de disfunção autônoma em professores e sua relação com as queixas vocais e as variáveis ocupacionais / Signs and symptoms of autonomic dysfunction in teachers and its relation tovoice complaints and occupational variables / Signos y síntomas de disfunción autonómica en docentes y su relación con sus las quejas vocales y las variables ocupacionales

Objetivo: descrever a ocorrência, correlacionar e associar os sinais e sintomas de disfunção autônoma relacionados à voz com as características ocupacionais, queixas vocais, sexo e idade de um grupo de professores. Material e Método: 114 indivíduos, com idade entre 20 e 66 anos, média de 37,76 anos, sendo 102 mulheres e 12 homens. Os participantes responderam ao Protocolo de Disfunção Autônoma (PDA), sendo coletados também dados de identificação, ocupacionais e queixas vocais. Os dados foram analisados estatisticamente por meio dos testes não paramétricos Correlação de Pearson e ANOVA, com intervalo de significância de 5%. Resultados: os professores apresentaram tempo médio de utilização da voz profissional de 12,7 anos, trabalhando em média 6,96 horas diárias. Houve média de 16,89 sintomas com relação direta com a voz. Não houve correlação dos sinais e sintomas de disfunção autônoma com idade, tempo de atuação profissional e utilização diária da voz ou associação com a rede de ensino em que os professores atuavam. Houve associação entre a média dos escores dos domínios de sinais esintomas de disfunção autônoma com o sexo feminino e a presença de queixas vocais. Conclusão: No grupo de professores estudado, a média de ocorrência de sintomas sem relação com a voz foi de 24,72; de sintomas com relação direta com a voz foi de 16,89 e de questões não relevantes foi de 5,32. Mulheres e indivíduos que apresentavam queixas vocais mostraram mais sinais e sintomas de disfunção autônoma

Objective: describe the occurrence, correlate and associate the signs and symptoms of autonomic dysfunction related to voice with the occupational characteristics, vocal complaints, sex and age of a group of teachers. Material and Method: 114 individuals, aged between 20 and 66 years, mean 37,76 years, with 102 women and 12 men. The participants answered the Questionnaire of Autonomic Dysfunction (QAD), and also collected identification data, occupational and vocal complaints. Data were analyzed statistically using the nonparametric ANOVA and Pearson correlation, with an interval of 5% significance. Results: teachers had average duration of use of the professional voice of 12,7 years, working on average 6,96 hours daily. There was an average of 16,89 with symptoms directlyrelated to the voice. There was no correlation of the signs and symptoms of autonomic dysfunction with age, time of practice and daily use of voice or association with the schools in which teachers worked. There was an association between the mean domain scores of signs and symptoms of autonomic dysfunction with the female and the presence of vocal. Conclusion: in the group of teachers studied, the average occurrence of symptoms unrelated to the voice was 24,72; symptom reporting directly to the voice was 16,89 and not relevant questions was 5,32. Women andindividuals with vocal complaints showed more signs and symptoms of autonomic dysfunction

Objetivo: describir la ocurrencia, correlacionar y asociar los signos y síntomas de disfunción autonómica relacionadas con la voz con las características ocupacionales, quejas vocales, sexo y edad de un grupo de profesores. Material y método: 114 individuos, con edades comprendidas entre 20 y 66 años, media de 37,76 años, con 102mujeres y 12 hombres. Los participantes respondieron el ?Protocolo de Disfunção Autonoma? (PDA), y también se recogieron los datos de identificación, ocupacional y quejas vocales. Los datos se analizaron estadísticamente usando el ANOVA no paramétrico y de correlación de Pearson, con un intervalo de 5% de significancia. Resultados:profesores tenían duración media de uso de la voz profesional de 12,7 años, trabajando en promedio 6,96 horas al día. Hubo un promedio de 16,89 con síntomas directamente relacionados con la voz. No hubo correlación de los signos y síntomas de disfunción autonómica con la edad, el tiempo de la práctica y el uso diario de la voz o de la asociación con las escuelas en las que los profesores trabajaban. Hubo una asociación entre las puntuaciones medias de dominio de los signos y síntomas de disfunción autonómica con la hembra y la presencia de quejas vocales. Conclusión: en el grupo de los profesores estudiado, la incidencia media de síntomas no relacionados con la voz era 24,72; síntoma que depende directamente la voz era 16,89 y no a las preguntas pertinentes era 5,32. Mujeres y personas con quejas vocales mostraron más signos y síntomas de disfunción autonómica

Inner ear symptoms: can we use them to approach cardiovascular diseases?

Sensory organs are programmed to detect external stimuli, and inform about possible threats. In general, they are characterized by a complex architecture, a highly energy-requiring function, a peripheral location and a vascular supply depending on a terminal circulation usually under systemic control. Their function may be highly sensitive to more general disorders primarily involving other organs or physiological systems. Consequently, the onset of transient or persistent symptoms of impairment of sensory organs might be the expression of abnormalities in the integrity of more general systems, especially in the elderly population. In the otologic area, despite the availability of evidence supporting the negative impact of some systemic conditions negatively affecting the local blood supply at the labyrinth level, the possibility that the inner ear can reveal the presence of sub-clinical, non-otologic disorders has never been the topic of a constructive investigation. The present review summarizes the preliminary available evidence suggesting a possible negative impact of early systemic hemodynamic changes on the function of the inner ear, as well as the possibility that some audiological symptoms may play some role in the early detection of cardiovascular diseases. In particular, we hypothesize that some cardiovascular diseases may cause an impairment in correct labyrinthine function as a result of a negative interaction between systemic hemodynamic changes, a reflex activation of the autonomic nervous system, and a local vascular response. A multidisciplinary approach to the interpretation of inner ear disorders may increase the possibility of an earlier recognition and understanding of systemic dysfunctions in clinical practice.

Sudden death of an infant with cardiac, nervous system and genetic involvement--a case report.

We present a case of sudden death of a 1-month-old male infant with heart, brainstem and genetic polymorphism involvement. Previously considered quite healthy, the child died suddenly and unexpectedly during sleep. The autopsy protocol included an in-depth anatomopathological examination of both the autonomic nervous system and the cardiac conduction system, and molecular analysis of the serotonin transporter gene promoter region, in which a specific genetic condition seems to be associated with sudden infant death. Histological examination revealed the presence of congenital cardiac alterations (hypertrophic cardiomyopathy and an accessory Mahaim fiber in the cardiac conduction system), severe hypodevelopment of all the raphe nuclei and a heterozygous genotype L/S related to the serotonin transporter gene. The sudden death of this infant was the unavoidable outcome of a complex series of congenital anomalies, each predisposing to SIDS. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3480540091031788.

Primary Sjogrens syndrome is associated with impaired autonomic response to orthostasis and sympathetic failure.

BACKGROUND: Symptoms in keeping with autonomic dysfunction are commonly described by primary Sjögrens syndrome patients (pSS); whether objective abnormalities of autonomic function occur is unclear. This study set out to explore dynamic cardiovascular autonomic responses in pSS and their relationship with symptoms and quality of life. METHODS: Twenty-one people from the UK pSS registry, 21 community controls and 21 patients with the autoimmune liver disease primary biliary cirrhosis (PBC) (matched case-wise for age and sex) attended for assessment of autonomic responses to orthostasis and Valsalva manoeuvre (VM). pSS patients also completed EULAR Sjögrens Syndrome patient-reported index (ESSPRI), EULAR Sjögren's syndrome disease activity index (ESSDAI), fatigue impact scale and EURO-QOL 5-dimension (EQ-5D). RESULTS: Compared with controls, pSS patients had significantly lower baseline systolic blood pressure (SBP) (114 ± 13 vs. 127 ± 20; P = 0.02), which dropped to a significantly lower value (98 ± 22 vs. 119 ± 24, P = 0.009). When area under the curve (AUC) was calculated for when the SBP was below baseline this was significantly greater in pSS compared to both control groups (pSS vs. control vs. PBC: 153 ± 236 vs. 92 ± 85 vs. 1.2 ± 0.3, P = 0.005). Peak phase IV SBP during the VM was significantly lower in pSS (P = 0.007) indicating early sympathetic failure. Increased heart rate associated with fatigue (P = 0.02; r(2) = 0.2) and EQ-5D. A shift in sympathetic-vagal balance associated with overall symptom burden (ESSPRI) (P = 0.04, r(2) = 0.3) and EULAR sicca score (P = 0.016; r(2) = 0.3), the latter also correlated with baroreceptor effectiveness (P = 0.03; r(2) = 0.2) and diastolic blood pressure variability (P = 0.003; r(2) = 0.4). CONCLUSION: pSS patients have impaired blood pressure response to standing. Dysautonomia correlates with PSS-associated symptoms and quality of life.

Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice.

The receptor tyrosine kinase ret protooncogene (RET) is implicated in the pathogenesis of several diseases and in several developmental defects, particularly those in neural crest-derived structures and the genitourinary system. In order to further elucidate RET-mediated mechanisms that contribute to these diseases and decipher the basis for specificity in the pleiotropic effects of RET, we characterized development of the enteric and autonomic nervous systems in mice expressing RET9 or RET51 isoforms harboring mutations in tyrosine residues that act as docking sites for the adaptors Plcgamma, Src, Shc, and Grb2. Using this approach, we found that development of the genitourinary system and the enteric and autonomic nervous systems is dependent on distinct RET-stimulated signaling pathways. Thus, mutation of RET51 at Y1062, a docking site for multiple adaptor proteins including Shc, caused distal colon aganglionosis reminiscent of Hirschsprung disease (HSCR). On the other hand, this mutation in RET9, which encodes an isoform that lacks the Grb2 docking site present in RET51, produced severe abnormalities in multiple organs. Mutations that abrogate RET-Plcgamma binding, previously shown to produce features reminiscent of congenital anomalies of kidneys or urinary tract (CAKUT) syndrome, produced only minor abnormalities in the nervous system. Abrogating RET51-Src binding produced no major defects in these systems. These studies provide insight into the basis of organotypic specificity and redundancy in RET signaling within these unique systems and in diseases such as HSCR and CAKUT.

Síndrome del dolor regional complejo / Complex regional pain syndrome

El síndrome de dolor regional complejo (SDRC) es una neuropatía crónica dolorosa progresiva con disfunción del sistema nervioso autónomo, desmineralizacion ósea y debilidad muscular; cuya aparición se asocia a algún evento traumático (fractura, cirugía o evento cardiovascular, etc.). Su diagnostico es fundamentalmente por interrogatorio y examen físico y se basa en el reconocimiento de algunas de las tres etapas clínicas clásicamente descriptas, predominando en las tempranas el dolor y los cambios autonómicos, y en las tardías, la atrofia y la pérdida de la funcionalidad. El pronóstico de la enfermedad es mejor cuando el diagnóstico es precoz (ej. durante la primera etapa) lo que minimiza las secuelas en el largo plazo. El tratamiento es interdisciplinario, siendo clave proporcionar alivio al dolor y la participación de personal entrenado en rehabilitación neuromuscular y/u ocupacional, con el objetivo de preservar y recuperar la funcionalidad perdida.

Síndrome del dolor regional complejo / Complex regional pain syndrome

El síndrome de dolor regional complejo (SDRC) es una neuropatía crónica dolorosa progresiva con disfunción del sistema nervioso autónomo, desmineralizacion ósea y debilidad muscular; cuya aparición se asocia a algún evento traumático (fractura, cirugía o evento cardiovascular, etc.). Su diagnostico es fundamentalmente por interrogatorio y examen físico y se basa en el reconocimiento de algunas de las tres etapas clínicas clásicamente descriptas, predominando en las tempranas el dolor y los cambios autonómicos, y en las tardías, la atrofia y la pérdida de la funcionalidad. El pronóstico de la enfermedad es mejor cuando el diagnóstico es precoz (ej. durante la primera etapa) lo que minimiza las secuelas en el largo plazo. El tratamiento es interdisciplinario, siendo clave proporcionar alivio al dolor y la participación de personal entrenado en rehabilitación neuromuscular y/u ocupacional, con el objetivo de preservar y recuperar la funcionalidad perdida.(AU)

Cintilografia miocárdica com I¹²³-MIBG na Avaliação da Insuficiência Cardíaca / ¹²³-MIBG myocarduial scintigraphy in heart failure assessment

O sistema nervoso autônomo (SNA) desempenha um papel fundamental na regulação da fisiologia cardiovascular, atuando sobre o cronotropismo, inotropismo, dromotropismo, resistência vascular e fluxo sanguíneo miocárdico, tanto em indivíduos saudáveis como em portadores de cardiopatias. Entretanto, o desequilíbrio entre os sistemas simpático e parassimpático, com hiperestimulação adrenérgica e consequente aumento dos níveis de catecolaminas circulantes, constitui a principal condição fisiopatológica da insuficiência cardíaca, responsável por progressão da doença arritmias ventriculares e morte súbita. A neurotransmissão adrenérgica cardíaca...

In vivo requirement of TGF-beta/GDNF cooperativity in mouse development: focus on the neurotrophic hypothesis.

Neurotrophic factors are well-recognized extracellular signaling molecules that regulate neuron development including neurite growth, survival and maturation of neuronal phenotypes in the central and peripheral nervous system. Previous studies have suggested that TGF-beta plays a key role in the regulation of neuron survival and death and potentiates the neurotrophic activity of several neurotrophic factors, most strikingly of GDNF. To test the physiological relevance of this finding, TGF-beta2/GDNF double mutant (d-ko) mice were generated. Double mutant mice die at birth like single mutants due to kidney agenesis (GDNF-/-) and congential cyanosis (TGF-beta2-/-), respectively. To test for the in vivo relevance of TGF-beta2/GDNF cooperativity to regulate neuron survival, mesencephalic dopaminergic neurons, lumbar motoneurons, as well as neurons of the lumbar dorsal root ganglion and the superior cervical ganglion were investigated. No loss of mesencephalic dopaminergic neurons was observed in double mutant mice at E18.5. A partial reduction in neuron numbers was observed in lumbar motoneurons, sensory and sympathetic neurons in GDNF single mutants, which was further reduced in TGF-beta2/GDNF double mutant mice at E18.5. However, TGF-beta2 single mutant mice showed no loss of neurons. These data point towards a cooperative role of TGF-beta2 and GDNF with regard to promotion of survival within the peripheral motor and sensory systems investigated.

Topological changes of the human autonomic cardiac nervous system in individuals with a retroesophageal right subclavian artery: two case reports and a brief review.

The topological changes of the human autonomic cardiac nervous system in two cadavers with a retroesophageal right subclavian artery (Rersa) were compared with the normal autonomic cardiac nervous system. The following new results were obtained in addition to the conventional deficient finding of the right recurrent laryngeal nerve. (1) Right superior cardiac nerves arising from the superior cervical ganglion were consistently observed in both cadavers, in addition to the right thoracic cardiac nerves along the Rersa. (2) A segmental accompanying tendency of the right cardiac nerves was recognized: the cardiac nerves arising from the sympathetic trunk cranial to the middle cervical ganglia ran along with the right common carotid artery, whereas the cardiac nerves arising from the sympathetic trunk caudal to the vertebral ganglion ran along the Rersa. (3) The right thoracic cardiac nerves, which have never been observed to accompany the normal right subclavian artery, ran along the proximal part of the Rersa. According to previous reports of individuals with the Rersa, a thick right thoracic cardiac nerve is commonly observed instead of a right superior cardiac nerve. However, all the cardiac nerves were recognized in both the individuals described in the present report. Therefore, we strongly disagree with the previous idea that the origin of the right cardiac nerves from the sympathetic trunk and ganglia is shifted caudally in individuals with the Rersa. The topological changes of the autonomic cardiac nervous system in two cases of Rersa also reflected spatial changes of great arteries.

Techniques and criteria in pathologic and forensic-medical diagnostics in sudden unexpected infant and perinatal death.

For each case of sudden infant and perinatal death, a full review of clinical and epidemiologic data and a complete necropsy study were performed according to the necropsy protocol devised by the Institute of Pathology, University of Milan, Milan, Italy (available at: http://users.unimi.it/~pathol/sids_e.html). Histopathologic examination of unexpected late fetal and neonatal death and SIDS cases allowed us to identify frequent alterations, mainly congenital, of the autonomic nervous system, modulating respiratory, cardiovascular, arousal, and upper digestive activities. The data and arguments presented herein provide a brief survey tending to open, rather than conclude, a far-reaching subject and to motivate medicolegal specialists and pathologists to perform more in-depth study.

Activity of the neurohormonal system and its relationship to autonomic abnormalities in decompensated heart failure.

BACKGROUND: The syndrome of congestive heart failure (CHF) entails complex autonomic and hormonal responses. Profound abnormalities in autonomic function, characterized by sympathetic overactivity and parasympathetic withdrawal, exert direct deleterious effects on the heart and contribute to progressive circulatory failure. We investigated the relationship of heart rate variability (HRV) with levels of neurohormones in plasma. METHODS AND RESULTS: We studied 64 patients admitted to the hospital for treatment of decompensated CHF (mean age, 59 +/- 2 years; New York Heart Association class III [72%] and IV [28%]). Time- and frequency-domain HRV indices were obtained from 24-hour Holter recordings. Neurohormonal activation was assessed by measuring plasma renin activity and aldosterone and norepinephrine levels. In the time domain, norepinephrine correlated negatively with average NN interval (r = -.34; P =.007), SDNN (r = -.35; P =.005), and SDANN (r = -.36; P =.004). In the frequency domain, norepinephrine was negatively associated with the total power (r = -.39; P =.001) and ultralow power (r = -.43; P =.0005). No correlation was found between indices indicative of parasympathetic modulation, except for a borderline correlation with the high-frequency power (r = -.25; P =.048). CONCLUSIONS: Reduced HRV may be associated with increased norepinephrine levels in patients with severe CHF. The ability of long-term HRV parameters to reflect in part the activation of diverse hormonal systems may explain their greater prognostic power for risk stratification in patients with CHF.

Evolución de los perímetros del iris y de la pupila fetal durante la gestación / Evolution of the perimeters of the iris and of the fetal pupil throughout gestation

Objetivo: La actividad pupilar depende del sistema nervioso autónomo y su regulación llega a alcanzar el córtex cerebral. En este artículo se estudia la evolución funcional del iris fetal en condiciones basales.Sujetos y métodos: Se examinaron mediante ultrasonidos 192 pupilas de fetos humanos desde las semanas 15 hasta la 42. Las imágenes eran digitalizadas para la medición informática de los perímetros de la pupila y del iris.Resultados: El perímetro del iris presenta un progreso lineal durante la gestación. El perímetro de la pupila muestra una evolución variable. A partir de la semana 23, el perímetro pupilar con relación al del iris es menor al 30 por 100. Esta relación, perímetro pupilar/iris, presenta una variación estadísticamente significativa a lo largo de la gestación (test de Kruskal-Wallis).Conclusiones: La actividad pupilar manifiesta una integridad de determinadas vías neurológicas y puede permitir un nuevo control neurológico de los fetos humanos (AU)

Estudo da variabilidade da frequência cardíaca em dois voluntários de meia-idade, um coronariopata e outro saudável: relato de caso / Study of the heart rate variability in two middle-aged men, one with heart disease and another healthy: case report

A utilidade clínica da variabilidade da frequência cardíaca para a identificaçäo de alteraçöes do sistema nervoso autônomo nas doenças do coraçäo tem sido reforçada por meio da implementaçäo de diferentes métodos de estudo da variabilidade. Neste estudo, procurou-se avaliar as diferenças entre a variabilidade da frequência cardíaca em repouso e em exercício de dois voluntários de meia-idade, um coronariopata e outro saudável, utilizando-se índices de variabilidade RMSM e RMSSD, bem como comparar sua relaçäo com a capacidade física dos voluntários. Os resultados demonstraram que o voluntário coronariopata apresentou menor variabilidade da frequência cardíaca tanto em repouso como em exercício, maior valor absoluto de frequência cardíaca de repouso e menor elevaçäo rápida desses valores no início do exercício, comparativamente ao voluntário saudável, sinais esses que sugerem alteraçöes na modulaçäo parassimpática do voluntário coronariopata.

6-Hydroxydopamine induced cardiac malformations and alterations of the autonomic nervous system in the developing chicken embryo.

6-Hydroxydopamine (6-OHDA) was injected into the air sac of developing chicken embryos on day E3 in order to study its effects on cardiac development both morphologically and biochemically. A dose-dependent teratogenic effect and fetotoxicity were observed in the 6-OHDA-treated embryos. Cardiac malformations, including ventricular septal lesions, detachment of the apical portions of the ventricles, cardiac hypertrophy, areas of coagulative necrosis with pyknotic nuclei and broken nuclear membranes, and swollen mitochondria were evident from gross histologic and ultrastructural examinations. A LD50 of 0.3 mg/egg on day E11 was obtained. Biochemically, 6-OHDA induced a significant dose-dependent reduction in the total cardiac choline acetyltransferase (ChAT) activities on days E8 and E11, followed by a recovery on days E15 and E20. The effects on muscarinic acetylcholine receptors (mAChRs) were less marked than on ChAT, indicating the effects on the cholinergic nervous system development are primarily presynaptic. There was a significant decrease in the level of norepinephrine (NE) and a delay in the appearance of detectable cardiac NE. It is suggested that 6-OHDA-induced cardiac malformation can be a useful model to study the mechanisms of cardiovascular development.