Genetic mapping of a new heart rate QTL on chromosome 8 of spontaneously hypertensive rats

Abstract Background Tachycardia is commonly observed in hypertensive patients, predominantly mediated by regulatory mechanisms integrated within the autonomic nervous system. The genetic loci and genes associated with increased heart rate in hypertension, however, have not yet been identified. Methods An F2 intercross of Spontaneously Hypertensive Rats (SHR) × Brown Norway (BN) linkage analysis of quantitative trait loci mapping was utilized to identify candidate genes associated with an increased heart rate in arterial hypertension. Results Basal heart rate in SHR was higher compared to that of normotensive BN rats (365 ± 3 vs. 314 ± 6 bpm, p < 0.05 for SHR and BN, respectively). A total genome scan identified one quantitative trait locus in a 6.78 cM interval on rat chromosome 8 (8q22–q24) that was responsible for elevated heart rate. This interval contained 241 genes, of which 65 are known genes. Conclusion Our data suggest that an influential genetic region located on the rat chromosome 8 contributes to the regulation of heart rate. Candidate genes that have previously been associated with tachycardia and/or hypertension were found within this QTL, strengthening our hypothesis that these genes are, potentially, associated with the increase in heart rate in a hypertension rat model.

Desnutrição perinatal e o controle hipotalâmico do comportamento alimentar e do metabolismo do músculo esquelético

A deficiência de nutrientes durante os períodos críticos do desenvolvimento tem sido associada com maior risco para desenvolver obesidade e diabetes Mellitus na vida adulta. Um dos mecanismos propostos refere-se à regulação do comportamento alimentar e às alterações do metabolismo energético do músculo esquelético. Recentemente, tem sido proposta a existência de uma comunicação entre o hipotálamo e o músculo esquelético a partir de sinais autonômicos que podem explicar as repercussões da desnutrição perinatal. Assim, esta revisão tem como objetivo discutir as repercussões da desnutrição perinatal sobre o comportamento alimentar e o metabolismo energético muscular e a comunicação existente entre o hipotálamo e o músculo via sinais adrenérgicos. Foram utilizadas as bases de dados MedLine/PubMed, Lilacs e Bireme, com publicações entre 2000 e 2011. Os termos de indexação utilizados foram: feeding behavior, energy metabolism, protein malnutrition, developmental plasticity, skeletal muscle e autonomic nervous system. Concluiu-se que a desnutrição perinatal pode atuar no controle hipotalâmico do comportamento alimentar e no metabolismo energético muscular, e a comunicação hipotálamo-músculo pode favorecer o desenvolvimento de obesidade e comorbidades durante o desenvolvimento.

Foetal heart rate recording: analysis and comparison of different methodologies

Monitoring foetal health is a very important task in clinical practice to appropriately plan pregnancy management and delivery. In the third trimester of pregnancy, ultrasound cardiotocography is the most employed diagnostic technique: foetal heart rate and uterine contractions signals are simultaneously recorded and analysed in order to ascertain foetal health. Because ultrasound cardiotocography interpretation still lacks of complete reliability, new parameters and methods of interpretation, or alternative methodologies, are necessary to further support physicians’ decisions. To this aim, in this thesis, foetal phonocardiography and electrocardiography are considered as different techniques. Further, variability of foetal heart rate is thoroughly studied. Frequency components and their modifications can be analysed by applying a time-frequency approach, for a distinct understanding of the spectral components and their change over time related to foetal reactions to internal and external stimuli (such as uterine contractions). Such modifications of the power spectrum can be a sign of autonomic nervous system reactions and therefore represent additional, objective information about foetal reactivity and health. However, some limits of ultrasonic cardiotocography still remain, such as in long-term foetal surveillance, which is often recommendable mainly in risky pregnancies. In these cases, the fully non-invasive acoustic recording, foetal phonocardiography, through maternal abdomen, represents a valuable alternative to the ultrasonic cardiotocography. Unfortunately, the so recorded foetal heart sound signal is heavily loaded by noise, thus the determination of the foetal heart rate raises serious signal processing issues. A new algorithm for foetal heart rate estimation from foetal phonocardiographic recordings is presented in this thesis. Different filtering and enhancement techniques, to enhance the first foetal heart sounds, were applied, so that different signal processing techniques were implemented, evaluated and compared, by identifying the strategy characterized on average by the best results. In particular, phonocardiographic signals were recorded simultaneously to ultrasonic cardiotocographic signals in order to compare the two foetal heart rate series (the one estimated by the developed algorithm and the other provided by cardiotocographic device). The algorithm performances were tested on phonocardiographic signals recorded on pregnant women, showing reliable foetal heart rate signals, very close to the ultrasound cardiotocographic recordings, considered as reference. The algorithm was also tested by using a foetal phonocardiographic recording simulator developed and presented in this research thesis. The target was to provide a software for simulating recordings relative to different foetal conditions and recordings situations and to use it as a test tool for comparing and assessing different foetal heart rate extraction algorithms. Since there are few studies about foetal heart sounds time characteristics and frequency content and the available literature is poor and not rigorous in this area, a data collection pilot study was also conducted with the purpose of specifically characterising both foetal and maternal heart sounds. Finally, in this thesis, the use of foetal phonocardiographic and electrocardiographic methodology and their combination, are presented in order to detect foetal heart rate and other functioning anomalies. The developed methodologies, suitable for longer-term assessment, were able to detect heart beat events correctly, such as first and second heart sounds and QRS waves. The detection of such events provides reliable measures of foetal heart rate, potentially information about measurement of the systolic time intervals and foetus circulatory impedance.

Caratterizzazione dei sintomi neurovegetativi e neuropsicologici nella malattia di Parkinson associata a mutazioni del gene glucocerebrosidasi

Pochi studi hanno indagato il profilo dei sintomi non-motori nella malattia di Parkinson associata al gene glucocerebrosidasi (GBA). Questo studio è mirato alla caratterizzazione dei sintomi non-motori, con particolare attenzione alla valutazione delle funzioni neurovegetativa, cognitiva e comportamentale, nel parkinsonismo associato a mutazione del gene GBA con la finalità di verificare se tali sintomi non-motori siano parte dello spettro clinico di questi pazienti. E’ stato condotto su una coorte di pazienti affetti da malattia di Parkinson che erano stati tutti sottoposti ad una analisi genetica per la ricerca di mutazioni in uno dei geni finora associati alla malattia di Parkinson. All’interno di questa coorte omogenea sono stati identificati due gruppi diversi in relazione al genotipo (pazienti portatori della mutazione GBA e pazienti non portatori di nessuna mutazione) e le caratteristiche non-motorie sono state confrontate nei due gruppi. Sono state pertanto indagati il sistema nervoso autonomo, mediante studio dei riflessi cardiovascolari e analisi dei sintomi disautonomici, e le funzioni cognitivo-comportamentali in pazienti affetti da malattia di Parkinson associata a mutazione del gene GBA. I risultati sono stati messi a confronto con il gruppo di controllo. Lo studio ha mostrato che i pazienti affetti da malattia di Parkinson associata a mutazione del gene GBA presentavano maggiore frequenza di disfunzioni ortosimpatiche, depressione, ansia, apatia, impulsività, oltre che di disturbi del controllo degli impulsi rispetto ai pazienti non portatori. In conclusione, i pazienti GBA positivi possono esprimere una sintomatologia non-motoria multidominio con sintomi autonomici, cognitivi e comportamentali in primo piano. Pertanto l’impostazione terapeutica in questi pazienti dovrebbe includere una accurata valutazione dei sintomi non-motori e un loro monitoraggio nel follow up clinico, allo scopo di ottimizzare i risultati e ridurre i rischi di complicazioni.

Inflammation as a psychophysiological biomarker in chronic psychosocial stress

The measurement of inflammation by biomarkers not only documents clinically relevant infections but also offers an important tool to pin point potentially harmful effects of chronic psychosocial stressors. This article focuses firstly on basic biology of inflammation and lists main biomarkers currently used in psycho-physiologic research. In the second part, the effects of the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system as pathways modulating stress-related inflammation are discussed. Furthermore, current evidence of how chronic psychosocial stressors are related to alterations in inflammatory activity is presented. In summary, job stress, low socioeconomic status, childhood adversities as well as life events, caregiver stress, and loneliness were all shown to exert effects on immunologic activity.

An anatomical investigation of the cervicothoracic ganglion

Anatomical variability within the autonomic nervous system has long been accepted. This study evaluated the anatomical variability of the cervicothoracic ganglion (CTG) according to its form and, in addition, provided precise measurements between the CTG and the anterior tubercle of the transverse process of the sixth cervical vertebra (C6TP), the first costovertebral articulation, and the vertebral artery. Forty-two adult cadavers were dissected, 22 male and 20 females. Five main forms of CTG were documented; spindle (31.9%), dumbbell (23.2%), truncated (21.7%), perforated (14.5%), and inverted-L (8.7%). The means for length, width, and thickness of the CTG were 18.5 mm, 8.2 mm, and 4.5 mm, respectively. The dimensions were found to be slightly larger in the males than females and on the left sides as compared to the right. The mean shortest distance between the CTGs and the vertebral artery was found to be 2.8 mm, whilst the mean shortest distances to C6TP was 25.7 mm and to the first costovertebral articulation was 1.7 mm. There is great variability in the morphology of the CTG with five common forms consistently seen. The relation to the vertebral artery may influence the form of the ganglion. Two previously undocumented forms are recorded; the truncated which describes the important juxtaposition of the CTG and the vertebral artery and the perforated which describes the piercing of the ganglion itself by the artery. The findings are considered to be of clinical importance to anesthetists, surgeons, neurosurgeons, and anatomists.

Drug suicide: a sex-equal cause of death in 16 European countries

Background There is a lack of international research on suicide by drug overdose as a preventable suicide method. Sex- and age-specific rates of suicide by drug self-poisoning (ICD-10, X60-64) and the distribution of drug types used in 16 European countries were studied, and compared with other self-poisoning methods (X65-69) and intentional self-injury (X70-84). Methods Data for 2000-04/05 were collected from national statistical offices. Age-adjusted suicide rates, and age and sex distributions, were calculated. Results No pronounced sex differences in drug self-poisoning rates were found, either in the aggregate data (males 1.6 and females 1.5 per 100,000) or within individual countries. Among the 16 countries, the range (from some 0.3 in Portugal to 5.0 in Finland) was wide. 'Other and unspecified drugs' (X64) were recorded most frequently, with a range of 0.2-1.9, and accounted for more than 70% of deaths by drug overdose in France, Luxembourg, Portugal and Spain. Psychotropic drugs (X61) ranked second. The X63 category ('other drugs acting on the autonomic nervous system') was least frequently used. Finland showed low X64 and high X61 figures, Scotland had high levels of X62 ('narcotics and hallucinogens, not elsewhere classified') for both sexes, while England exceeded other countries in category X60. Risk was highest among the middle-aged everywhere except in Switzerland, where the elderly were most at risk. Conclusions Suicide by drug overdose is preventable. Intentional self-poisoning with drugs kills as many males as females. The considerable differences in patterns of self-poisoning found in the various European countries are relevant to national efforts to improve diagnostics of suicide and appropriate specific prevention. The fact that vast majority of drug-overdose suicides came under the category X64 refers to the need of more detailed ICD coding system for overdose suicides is needed to permit better design of suicide-prevention strategies at national level.

Music, perceived arousal, and intensity: psychophysiological reactions to Chopin's "Tristesse"

The present study investigates the relation of perceived arousal (continuous self-rating), autonomic nervous system activity (heart rate, heart rate variability) and musical characteristics (sound intensity, musical rhythm) upon listening to a complex musical piece. Twenty amateur musicians listened to two performances of Chopin's "Tristesse" with different rhythmic shapes. Besides conventional statistical methods for analyzing psychophysiological reactions (heart rate, respiration rate) and musical variables, semblance analysis was used. Perceived arousal correlated strongly with sound intensity; heart rate showed only a partial response to changes in sound intensity. Larger changes in heart rate were caused by the version with more rhythmic tension. The low-/high-frequency ratio of heart rate variability increased-whereas the high frequency component decreased-during music listening. We conclude that autonomic nervous system activity can be modulated not only by sound intensity but also by the interpreter's use of rhythmic tension. Semblance analysis enables us to track the subtle correlations between musical and physiological variables.

Day-to-night time differences in the relationship between cardiorespiratory coordination and heart rate variability

Heart rate variability (HRV) and cardiorespiratory coordination, i.e. the temporal interplay between oscillations of heartbeat and respiration, reflect information related to the cardiovascular and autonomic nervous system. The purpose of this study was to investigate the relationship between spectral measures of HRV and measures of cardiorespiratory coordination. In 127 subjects from a normal population a 24 h Holter ECG was recorded. Average heart rate (HR) and the following HRV parameters were calculated: very low (VLF), low (LF) and high frequency (HF) oscillations and LF/HF. Cardiorespiratory coordination was quantified using average respiratory rate (RespR), the ratio of heart rate and respiratory rate (HRR), the phase coordination ratio (PCR) and the extent of cardiorespiratory coordination (PP). Pearson's correlation coefficient r was used to quantify the relationship between each pair of the variables across all subjects. HR and HRR correlated strongest during daytime (r = 0.89). LF/HF and PP showed a negative correlation to a reasonable degree (r = -0.69). During nighttime sleep these correlations decreased whereas the correlation between HRR and RespR (r = -0.47) as well as between HRR and PCR (r = 0.73) increased substantially. In conclusion, HRR and PCR deliver considerably different information compared to HRV measures whereas PP is partially linked reciprocally to LF/HF.

[What are the physical complaints without pathological clinical signs in patients with diabetes mellitus?]

In previous research it was found that patients with diabetes mellitus suffer from multiple physical symptoms even early in their disease course. Such complaints may relate to blood glucose levels or can be understood as a sign of distress in respect to the diagnosis of a chronic disease. PURPOSE: This study was performed to evaluate in a cross-sectional analysis all the symptoms that patients may complain of and to relate these symptoms to a possible dysfunction of the autonomic nervous system. METHOD: We assessed the complaints of 66 patients with diabetes mellitus and compared these variables with those of patients with psychological disturbances (n = 794) or somatic disease (n = 162). The symptoms were recorded by means of several questionnaires such as the "Giessener Beschwerdebogen" (GBB), "the Freiburger Persönlichkeitsinventar" (FPI), the German version of the State Trait Anxiety Inventory (STAI) and the German version of the State Trait Anger Expression Inventory (STAXI). The autonomic nervous system was assessed using resting and mental stress conditions in a subset of patients with diabetes mellitus (n = 29) and psychological disturbances (n = 44). RESULTS: Patients suffering from diabetes mellitus and psychological disturbances showed a tendency to higher scores in GBB, STAI and STAXI. As far as psychological disturbances are concerned, the complaints experienced by patients with diabetes mellitus were found to be similar to those with somatic diseases. Both groups, however, rate clearly below those with psychological disturbances. The results of autonomic testing showed a significant disturbance in patients with diabetes mellitus with reduced sensitivity of the baroreceptor indicating autonomic neuropathy. CONCLUSION: Some of the physical complaints of patients with diabetes mellitus can be understood in connection with autonomic dysfunction. Moreover, an explicitly psychological view of these complaints may not be correct.

Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality.

AIMS The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality. METHODS AND RESULTS We conducted a genome-wide association study on the methylarginine traits and investigated the predictive value of the new discovered variants on mortality. Our meta-analyses replicated the previously known locus for ADMA levels in DDAH1 (rs997251; P = 1.4 × 10(-40)), identified two non-synomyous polymorphisms for SDMA levels in AGXT2 (rs37369; P = 1.4 × 10(-40) and rs16899974; P = 1.5 × 10(-38)) and one in SLC25A45 (rs34400381; P = 2.5 × 10(-10)). We also fine-mapped the AGXT2 locus for further independent association signals. The two non-synonymous AGXT2 variants independently associated with SDMA levels were also significantly related with short-term heart rate variability (HRV) indices in young adults. The major allele (C) of the novel non-synonymous rs16899974 (V498L) variant associated with decreased SDMA levels and an increase in the ratio between the low- and high-frequency spectral components of HRV (P = 0.00047). Furthermore, the SDMA decreasing allele (G) of the non-synomyous SLC25A45 (R285C) variant was associated with a lower resting mean heart rate during the HRV measurements (P = 0.0046), but not with the HRV indices. None of the studied genome-wide significant variants had any major effect on cardiovascular or total mortality in patients referred for coronary angiography. CONCLUSIONS AGXT2 has an important role in SDMA metabolism in humans. AGXT2 may additionally have an unanticipated role in the autonomic nervous system regulation of cardiac function.

Pathophysiologie des Schmerzes und Neuraltherapie

Die Neuraltherapie nach Huneke ist eine Injektionsbehandlung, welche Lokalanästhetika zur Diagnostik und Therapie einsetzt. Je nach Situation erfolgt der Reiz (und/oder die Unterbrechung einer pathologischen Belastung) im Bereiche der Segmentreflektorik oder über das sogenannte Störfeld. Dieses kann ausserhalb jeder segmentalen Ordnung eine Erkrankung oder ein Schmerzbild auslösen und unterhalten. Mit der Neuraltherapie werden gezielt autoregulatorische Mechanismen des Vegetativums (insbesondere des Sympathikus) angesprochen. Theoretische Grundlagen hierzu sind Erkenntnisse aus der Neurophysiologie und der Modernen Physik.

Psychometric and biohormonal indices of dental anxiety in children. A prospective cohort study.

The stress of dental treatment often elicits negative emotions in children, expressed as dental fear or anxiety. Highly anxious children obstruct treatment and avoid therapy, further amplifying oral health problems. The aim of this study was to examine the neuroendocrine and autonomic nervous system responses to dental treatment and their possible interactions and associations with psychometric indices of anxiety, caries, previous dental experience, anesthesia, age and gender in school children. Upon informed consent, saliva was obtained from 97 children (59% males, mean age ±  SD: 89.73 ± 15 months) in the Clinic of pediatric dentistry before treatment, immediately post-treatment and at the recall visit to determine cortisol and salivary alpha-amylase (sAA) levels. Dental and general anxiety was assessed through specific questionnaires completed by the children. Compared to pre-treatment, cortisol levels were increased following treatment, while sAA levels were higher at the recall. Pre- and post-treatment cortisol and sAA responses were positively correlated. Dental and general anxiety questionnaire scores were also significantly correlated with each other. The integrated autonomic and neuroendocrine responses prior to treatment were correlated with state anxiety and those following treatment with dental anxiety. However, univariable and multivariable linear regression analysis associated post-treatment cortisol, but not sAA, levels with dental anxiety. No associations of cortisol or sAA responses with caries, age, gender, previous dental experience or anesthesia were detected. These data provide some evidence that both sAA and cortisol levels are altered in children in anticipation or during dental treatment, but only cortisol levels are associated to dental anxiety.

Influence of transrectal and transabdominal ultrasound examination on salivary cortisol, heart rate, and heart rate variability in mares

Pregnancy diagnostics in equine reproduction are routinely performed using transrectal ultrasonography, although it is also possible to visualize the fetus by transabdominal ultrasound examinations from the 90th day of gestation onward. We hypothesized that ultrasound examinations may stress the mare and that the gestational stage status and lactation may influence the mare's stress reaction. To investigate the stress reaction, 25 thoroughbred mares of different age, pregnancy and lactational status underwent a transrectal examination. In pregnant mares, an additional transabdominal examination was performed. Salivary cortisol concentration, mean heart rate, and heart rate variability of mares were assessed to evaluate the reactions of hypothalamic–pituitary–adrenal (HPA) axis and of the autonomic nervous system. Significant differences were observed between lactating and nonlactating mares; with a lower responsiveness to stress in lactating mares. The transrectal ultrasound examination in nonlactating mares induced a significant increase in salivary cortisol (P < 0.05), and in the heart rate variability parameter, ratio of low to high frequencies (P < 0.05). This reflects an activation of the HPA axis and a shift to more sympathetic dominance. In contrast, a transabdominally performed pregnancy check did not induce an activation of the HPA axis over basal level but increased the mean heart rate and low to high frequency ratio. The results of this study indicate that checks of advanced pregnancies can be easily performed by transabdominal ultrasonography. With regard to animal welfare, this technique should be preferred during midgestation in nonlactating mares.

Das Elektrokardiogramm des Sporttreibenden und der Sport-assoziierte plötzliche Herztod.

Regelmässiges körperliches Training induziert strukturelle, elektrische und funktionelle Anpassungen des Herzens. Die grösste Herausforderung für den Arzt liegt darin, Veränderungen hinweisend für eine strukturelle Herzerkrankung von physiologischen, trainingsassoziierten Anpassungen im Sinne eines 'Athlete's heart' zu unterscheiden. Bei zugrundliegender Kardiopathie ist sportliche Aktivität nicht die Ursache, sondern kann ein Trigger für belastungsabhängige Tachyarrhythmien bzw. für den belastungsabhängigen plötzlichen Herztod (SCD) sein. Um Athleten mit einer kardialen Grunderkrankung und erhöhtem Risiko für einen SCD frühzeitig zu identifizieren wird in Europa ein Preparticipation Screening empfohlen, welches von der Schweizerischen Gesellschaft für Sportmedizin (SGSM) übernommen wurde. Dieses Screening umfasst neben der spezifischen Anamnese und der Herzauskultation auch ein Ruhe-Elektrokardiogramm (Ruhe-EKG). Aufgrund der hohen Anzahl falsch-positiver EKG-Befunde wurden in den letzten Jahren die Beurteilungskriterien des Athleten-EKGs wiederholt angepasst, die Sensitivität und insbesondere auch die Spezifität konnte mit den „verfeinerten Seattle Kriterien“ 2014 deutlich verbessert werden. Der frühen Repolarisation galt in den letzten Jahren ein Hauptaugenmerk: neben dem (Ausdauer-) Training besteht eine klare Assoziation zum männlichen Geschlecht, zur Ethnie, zu den Veränderungen des vegetativen Nervensystems und zu erhöhten QRS-Voltage-Kriterien.