Impaired Parasympathetic Activity Research Articles

Reduced heart rate variability is associated with altered clinical laboratory profile in people living with HIV

BackgroundWe compared heart rate variability (HRV) indices between people living with HIV (PLWH) and HIV-negative individuals to ascertain the independent association between HIV infection and reduced HRV, and further investigated whether distinct clinical laboratory profiles exist between PLWH with and without reduced HRV. MethodsThis cross-sectional analysis included 304 PLWH and 147 HIV-negative individuals with comparable age and sex. Thirty-two routine clinical laboratory indices (including hematology and biochemistry) closest to the survey were extracted from the Electronic Medical Record System. HRV indices were divided into two categories: low (lowest quartile, Q1) and moderate-to-high (combined, Q2‒Q4). ResultsThe time domain indices, ln(SDNN), ln(RMSSD), and ln(PNN50), as well as the frequency domain indices, ln(HF), ln(LF), and ln(VLF), were all significantly reduced in PLWH versus HIV-negative individuals (all p < 0.05). These associations remained for ln(SDNN), ln(PNN50), ln(HF) and ln(LF) even after adjusting for potential confounders in multivariable models. PLWH with low HRV indices exhibited distinct clinical laboratory profiles that were characterized by an elevation in fasting plasma glucose, white blood cell count, neutrophil count, neutrophil%, and a reduction in albumin, total protein, urine creatinine, lymphocyte%, red blood cell count (RBC) and nadir CD4 count. The final stepwise logistic regression models for low SDNN included older age, decreased total cholesterol levels, elevated neutrophil count, and the use of antidiabetic medications, whereas the final model for low LF included older age, reduced RBC and the use of antidiabetic medications. ConclusionPLWH exhibit impaired parasympathetic activity, as evidenced by reduced SDNN, PNN50, LF and HF. Furthermore, PLWH who have reduced HRV indices exhibits distinct clinical laboratory profiles that are related to systematic inflammatory response and diabetes.

Revealing functional-molecular parasympathetic dysfunction in PVC-induced cardiomyopathy via dual stressor PVC and exercise

Abstract Background Exercise intolerance is a common presentation of premature ventricular contractions-induced cardiomyopathy (PVC-CM). In a canine PVC-CM model, previous studies have shown cardiac autonomic nervous system remodeling, resulting in persistent sympathetic excess. Nevertheless, the molecular mechanisms and functional implications of this neural remodeling, as well as parasympathetic alterations, remain unclear. Purpose We aim to evaluate the functional-molecular mechanisms of parasympathetic remodeling and its potential contribution to exercise intolerance in an animal model of PVC-CM. Methods We studied 15 canines (8 experimental vs 7 sham controls) chronically instrumented with pacemakers and telemetry devices to deliver 12-weeks of bigeminal PVCs (200ms coupling) to induce PVC-CM and to record sympathetic (SNA), vagal nerve activity (VNA) and heart rate (HR) over this period. Exercise challenge was conducted in sinus rhythm (SR) and in the presence of bigeminal PVCs ("dual stressor") at baseline and after development of PVC-CM. Sympatho-vagal neural and HR responses were assessed during and after exercise at baseline and after PVC-CM development, with and without PVCs, thus comparing baseline SR, baseline with PVCs, CM SR and CM with PVCs. Western Blot was performed on intrinsic and extrinsic cardiac neural tissues to evaluate molecular mechanisms of neural remodeling. Results Compared to baseline, SNA was significantly higher in PVC-CM in all phases of exercise (rest, exercise, recovery, p=0.03). In contrast, VNA was significantly lower in PVC-CM than baseline during exercise recovery (P=0.014). After exercise, HR recovery (HRR) was impaired (p=0.001), VNA lower (p=0.014) and SNA (p=0.03) higher in PVC-CM compared with baseline. Tyrosine hydroxylase (TH) immunoreactivity in the left ventricle (LV, p=0.001) and stellate ganglia (SG, p=0.03) and trans-cardiac plasma NE levels (p=0.03) were higher in PVC-CM compared with sham. Choline Acetyltransferase (CHAT) was not significantly different in either vagus (p=0.33) or LV (p=0.8) between PVC-CM vs sham. Cardiac (LV) Nerve Growth Factor (NGF), Growth Associated Protein (GAP-43) and beta 1-adrenoreceptor levels were lower (p=0.042, p=0.003, p=0.002 respectively) whereas beta 2-adreno- and muscarinic M2-cholinergic receptors were higher (p=0.02, p&amp;lt;0.01 respectively) in PVC-CM compared with sham. Conclusion Neural remodeling in PVC-CM results in an imbalanced sympathetic excess and sympathetic-parasympathetic dysfunction characterized by a loss of sympathetic functional reserve during exercise and impaired parasympathetic activity and HRR after exercise. Adaptive downregulation of NGF might explain this imbalance and dysfunction. These data open the intriguing possibility of neural-targeted therapies to reverse remodeling and restore autonomic function disrupted by chronic PVCs.GraphsMolecular

Autonomic dysregulation in long-term patients suffering from Post-COVID-19 Syndrome assessed by heart rate variability

Post-COVID-19 Syndrome (PCS) is a condition with multiple symptoms partly related to dysregulation of the autonomic nerve system. Assessment of heart rate variability (HRV) using 24 h Holter-ECG may serve as a surrogate to characterize cardiac autonomic activity. A prospective study including 103 PCS patients (time after infection = 252 days, age = 49.0 ± 11.3 years, 45.7% women) was performed and patients underwent detailed clinical screening, cardiopulmonary exercise testing, and 24 h Holter monitoring. Data of PCS patients was compared to 103 CAD patients and a healthy control group (n = 90). After correction for age and sex, frequency-related variables differed in PCS patients compared to controls including LF/HFpower, LF/HFnu, and LF/HF ratio (24 h; p ≤ 0.001). By contrast, these variables were largely comparable between PCS and CAD patients, while sympathetic activation was highest in PCS patients during the 24 h period. Overall, PCS patients showed disturbed diurnal adjustment of HRV, with impaired parasympathetic activity at night. Patients hospitalized during acute infection showed an even more pronounced overactivation of sympathetic activity compared to patients who underwent ambulant care. Our data demonstrate persistent HRV alterations in PCS patients with long-term symptom duration, suggesting a sustained impairment of sympathovagal balance. Moreover, sympathetic overstimulation and diminished parasympathetic response in long-term PCS patients are comparable to findings in CAD patients. Whether HRV variables have a prognostic value in PCS and/or might serve as biomarkers indicating a successful interventional approach warrants further longitudinal studies.

Baroreflex activation therapy in patients with heart failure with reduced ejection fraction: a single-centre experience.

Heart failure with reduced ejection fraction (HFrEF) is associated with excessive sympathetic and impaired parasympathetic activity. The Barostim Neo™ device is used for electronical baroreflex activation therapy (BAT) to counteract autonomic nervous system dysbalance. Randomized trials have shown that BAT improves walking distance and reduces N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels at least in patients with only moderate elevation at baseline. Its impact on the risk of heart failure hospitalization (HFH) and death is not yet established, and experience in clinical routine is limited. We report on patient characteristics and clinical outcome in a retrospective, non-randomized single-centre registry of BAT in HFrEF. Patients in the New York Heart Association (NYHA) Classes III and IV with a left ventricular ejection fraction (LVEF) <35% despite guideline-directed medical therapy were eligible. Symptom burden, echocardiography, and laboratory testing were assessed at baseline and after 12months. Clinical events of HFH and death were recorded at routine clinical follow-up. Data are shown as number (%) or median (inter-quartile range). Between 2014 and 2020, 30 patients were treated with BAT. Median age was 67 (63-77) years, and 27 patients (90%) were male. Most patients (83%) had previous HFH. Device implantation was successful in all patients. At 12months, six patients had died and three were alive but did not attend follow-up. NYHA class was III/IV in 26 (87%)/4 (13%) patients at baseline, improved in 19 patients, and remained unchanged in 5 patients (P<0.001). LVEF improved from 25.5 (20.0-30.5) % at baseline to 30.0 (25.0-36.0) % at 12months (P=0.014). Left ventricular end-diastolic diameter remained unchanged. A numerical decrease in NT-proBNP [3165 (880-8085) vs. 1001 (599-3820) pg/mL] was not significant (P=0.526). Median follow-up for clinical events was 16 (10-33) months. Mortality at 1 (n=6, 20%) and 3years (n=10, 33%) was as expected by the Meta-Analysis Global Group in Chronic Heart Failure risk score. Despite BAT, event rate was high in patients with NYHA Class IV, NT-proBNP levels >1600pg/mL, or estimated glomerular filtration rate (eGFR) <30mL/min at baseline. NYHA class and eGFR were independent predictors of mortality. Patients with HFrEF who are selected for BAT are in a stage of worsening or even advanced heart failure. BAT appears to be safe and improves clinical symptoms and-to a modest degree-left ventricular function. The risk of death remains high in advanced disease stages. Patient selection seems to be crucial, and the impact of BAT in earlier disease stages needs to be established.

The environmental and social stress perception in autism spectrum disorder – focusing on stress coping mechanisms and gastrointestinal manifestations

IntroductionAutism spectrum disorder (ASD) is currently defined as persistent deficits in social communication and social interaction additional to repetitive behavioural patterns, and restrictive interests or activities. Several studies suggested that ASD is accompanied by defective perception and altered response to the environmental factors, including environmental and social stress. In this context, frequent reports addressed the manifestation of different stress-related behavioural and physiological patterns, such as restless leg syndrome, migraine, and functional gastrointestinal disorders (FGIDs). Thus, a major problem in ASD patients’ management could be related to the exacerbated effects of stress.ObjectivesIn this study, we aimed to find a correlation between the stress perception and response and the manifestation of some neurological and FGIDs in ASD.MethodsThe main scientific databases were screened for studies describing the effects of stress in autism patients and animal models. Exclusion criteria: (1) studies not written in English language; (2) not available as full text; (3) not describing stress response; and/or (2) functional gastrointestinal manifestations in autism.ResultsThe repetitive behaviours have a heterogenous pattern in both severity and manifestations, varying from repetitive motor movements and inflexible adherence to routines to hypo- or hyper-reactivity to exterior stimuli. Moreover, some studies describe repetitive behaviours as altered stress coping mechanisms meant to relieve anxious states – one of the main stress axis activation effects. We recently described some significantly reported FGID-like manifestations in ASD that could be the result of various abnormalities in the brain – gut interaction, such as impaired parasympathetic activity and increased endocrine stress response. In this context, there could be a correlation between the altered perception and response to stress and the FGID-like manifestations, as we previously described the stress axis implication in one of the most common FGID, irritable bowel syndrome – which is also frequently reported in ASD cases.ConclusionsIn ASD, the perception and response to environmental and social stress could be impaired. Thus, impaired stress coping mechanisms, defective stress axis, and altered behavior could lead to stress-specific manifestations, such as restless leg syndrome, migraine, and irritable bowel syndrome.Funding: *B. I.-M. and *R. M.-A. are supported by the Project POCU/993/6/13/153322 ”Suport educațional și formativ pentru doctoranzi și tineri cercetători în pregătirea inserției în piața muncii” of the European Social Fund through the Human Capital Operational ProgramDisclosure of InterestI. M. Balmus Grant / Research support from: B. I.-M. is supported by the Project POCU/993/6/13/153322 ”Suport educațional și formativ pentru doctoranzi și tineri cercetători în pregătirea inserției în piața muncii” of the European Social Fund through the Human Capital Operational Program., M. A. Robea Grant / Research support from: R. M.- A. is supported by the Project POCU/993/6/13/153322 ”Suport educațional și formativ pentru doctoranzi și tineri cercetători în pregătirea inserției în piața muncii” of the European Social Fund through the Human Capital Operational Program., R. Lefter: None Declared, A. Ciobica: None Declared, L. Gorgan: None Declared, C. Stanciu: None Declared, A. Trifan: None Declared

Transcriptomic profiling reveals connection to lung autonomic nervous system dysfunction and inflammation in pulmonary artery hypertension rats

Abstract Background Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by elevated pulmonary artery pressure, right ventricular failure, and premature death. Previous studies showed autonomic nervous system (ANS) such as sympathetic nerve overactivity or impaired parasympathetic activity was implicated in the pathogenesis of PAH. However, PA remodeling and molecular mechanisms involved in ANS in PAH remain unclear. Purpose To unravel transcriptional regulation, underlying genes and signaling pathways linking to ANS in PAH. Methods Publicly available two RNA sequencing (RNAseq) datasets and one single-cell RNA sequencing (scRNAseq) data of lung from rats with PAH induced by high-dose monocrotaline (MCT) were downloaded and reprocessed. For RNA-seq data, STAR and RSEM were used for read alignment and gene expression qualification. Differential expression genes (DEGs) were identified using DSEseq2, after which enrichment analyses were implemented by clusterProfiler. scRNAseq data were analyzed using Seurat. Results Two RNAseq datasets identified a total of 6,046 and 2,172 DEGs respectively, including 2,945 and 1,228 up-regulated and 3,101 and 944 down-regulated. Overlapped DEGs genes among datasets were 1,123 genes. Functional enrichment analysis of downregulated DEGs in one data pointed out many dysregulated pathways related to nerve system, such as nervous system process, neuron projection, integral component of synaptic membrane in MCT-induced PAH rat (Fig. 1a). Both RNAseq datasets supported upregulated DEGs were also involved in pathways related to ANS including humoral immune response and synapse pruning (P&amp;lt;0.001) (Fig. 1a). Intriguingly, all four genes (Trem2, C1qa, C1qb and C1qc) in synapse pruning were progressively upregulated with severe PAH condition (P&amp;lt;0.05) (Fig. 1b, c). And RT-PCR results confirmed the expression level of these four genes were remarkably increased in PAH rats (P&amp;lt;0.0001) (Fig. 1d). These four genes are known marker genes for macrophages from lung and microglial cell from brain. scRNAseq data of lungs demonstrated these four genes were significantly upregulated in alveolar macrophages from MCT-PAH rats (P&amp;lt;0.001) (Fig. 1e). However, the pathogenic mechanisms of these four genes in nerve fibers from lungs underlying PAH have never been studied and would be further explored using histological analysis in this study. Conclusions Integrated bioinformatic analysis indicated the association of lung nervous system with PAH. Further, we identified four genes implicated in nervous system, previously reported to link to immune system and provide novel insights into the mechanisms underlying relationship between lung ANS and inflammation in the pathogenesis of PAH. The pathogenetic mechanism of these four genes is being further investigated. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The National Natural Science Foundation of Chinathe Nature Science Foundation of Hubei Province

Differences in Nervous Autonomic Control in Response to a Single Session of Exercise in Bodybuilders Using Anabolic Androgenic Steroids.

Considering the role of autonomic nerve activity in blood pressure control, this study aimed to investigate the cardiac autonomic nerve responses after an aerobic exercise session in Anabolic Androgenic Steroids (AAS) users. Twenty men (AAS, n = 9; control group, n = 11) performed an aerobic exercise session (60 min, 70 to 80% of HRmax). Heart rate variability (HRV) was assessed before and during a 60-min post-exercise recovery period. RMSSD (root mean square successive difference of the RR intervals) and the LF/HF ratio (low frequency/high frequency spectra) were also evaluated. The Student's t-test for independent samples was used to compare differences between initial group characteristics. Repeated measures ANOVA was used to compare pre- and post-exercise HRV recovery (p < 0.05). AAS had a lower SDNN (standard deviation of the intervals) (40.8 ± 16.8 vs. 71.6 ± 24.7 ms; p = 0.04, d = 1.4) and a higher LF/HF (3.4 ± 2.1 vs. 1.8 ± 0.9%; p = 0.03, d = 0.9) before exercise. AAS and controls had similar RMSSD (14.0 ± 15.8 vs. 18.9 ± 12.1 ms; p = 0.20) and a LF/HF (2.8 ± 1.6 vs. 2.4 ± 1.2 ms; p = 0.41) immediately post-exercise. The between-groups comparison revealed a higher HF/LF at 30 min (4.3 ± 1.4 vs. 2.5 ± 1.3%; p = 0.008, d = 1.3) and 60 min (5.0 ± 2.2 vs. 2.3 ± 0.8%; p = 0.001, d = 1.6) for the AAS group in the recovery time. This study demonstrated impaired parasympathetic activity at rest and immediately after the exercise session as an adverse effect of AAS usage, but similar behavior regarding the restoration of sympathetic activity.

Characteristics of cardiovascular autonomic dysfunction and association with quality of life in patients with systemic lupus erythematosus

ObjectivesCardiovascular autonomic neuropathy (CAN) may affect the clinical course of SLE leading to reduced quality of life. CAN is assessed by heart rate variability (HRV) measures and cardiovascular autonomic reflex...

Reduced Parasympathetic Activity in Patients With Different Types of Congenital Heart Disease and Associations to Exercise Capacity

Current research indicates an imbalance in the autonomic nervous system (ANS) pathway activities in patients with congenital heart disease (CHD). The heart rate variability (HRV) is a measure to quantify activities of the parasympathetic and sympathetic branches. This study evaluated the parasympathetic activity by means of HRV in patients with CHD, regarding diagnostic subgroups and CHD severity, and the association to exercise capacity. From July 2016 to August 2018, a total of 222 patients with different types of CHD (28.4 ± 10.1 yr; 44% female) received breathing-controlled HRV measurement in the supine position. Based on 130 adjacent heartbeats, the root mean square of successive differences (RMSSD), a parasympathetic activity surrogate was estimated and log-transformed. Additionally, all patients underwent a cardiopulmonary exercise test. For comparison, a control group (CG) of 57 (29.0 ± 7.1 yr; 61% female) healthy volunteers was recruited. Patients with CHD exhibited reduced parasympathetic activity in comparison to the CG (lnRMSSD CHD: 3.55 ± 0.57 ms vs CG: 3.93 ± 0.55 ms; P < .001), with the lowest parasympathetic activity in patients with Fontan circulation (3.07 ± 0.54 ms; P < .001). Complex CHD (3.40 ± 0.54 ms) had worse values compared with patients with simple (3.87 ± 0.55 ms; P < .001) and moderate severity (3.74 ± 0.54 ms; P < .001). Better parasympathetic activity in CHD patients was associated with increased exercise capacity (r = 0.322; P < .001). Impaired parasympathetic activity suggests limited function of the ANS in patients with CHD. Further studies should focus on the association of exercise capacity and ANS to possibly improve parasympathetic activity and functional outcomes.

Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

BackgroundPathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe...

A Descriptive Review on the Prevalence of Gastrointestinal Disturbances and Their Multiple Associations in Autism Spectrum Disorder.

Background and Objectives: Gastrointestinal disturbances have been frequently, but not unanimously, reported in autism spectrum disorder (ASD) individuals. Thus, digestive symptoms, such as constipation, diarrhea, abdominal bloating, and pain have been reported to correlate to the various maladaptive behaviors in ASD children, such as irritability, social withdrawal, stereotypy, hyperactivity, and even language regression. In this context, the present study provides an overview on the prevalence of the gastrointestinal (GI) disorders in ASD and the correlation between these and ASD symptoms and comorbidities and subsequently discusses the metabolic and microbiome factors underlying the effects of GI disorders in ASD. Materials and Methods: For our analysis of GI symptoms in children with ASD, we have searched peer-reviewed journals from 2005 to 2017 in PubMed databases that addressed the specificity of GI symptoms in ASD and included correlations of GI and ASD symptoms. The criteria for inclusion were clear quantitative mentioning of GI modifications, GI symptoms correlation with specific ASD symptoms or comorbidities, an appropriate methodology for defining ASD, and larger size samples. For this topic, only studies on human patients and original research were considered. A subsequent search in PubMed databases in journals from 2000 to 2017 we analyzed 13 articles on the mechanisms underlying the impact of GI dysfunctions in ASD, including gut microbial dysbiosis, immune reactivity, genetics, and altered neurotransmitters on the gut–brain axis. Results: In the 18 original research studies that we selected out of an initial 327 studies, despite the different methodology, a predominant 83% highlighted the increased prevalence of GI symptoms in ASD patients. Constipation was most frequently cited, appearing in 12 of the studies (80%), followed by diarrhea reports in eight studies (53%). The association between cognitive and behavioral deficits and GI disorders was suggested in certain groups of ASD individuals. Conclusion: The evidence presented so far by numerous studies seems to indicate that GI dysfunctions are of particular relevance in ASD, underlined by various abnormalities along the nervous connections between the central nervous system and the gut, such as impaired parasympathetic activity and increased endocrine stress response. Sufficiently large size samples and standardized methodology are required for future studies to clarify the complex interactions between GI disturbances and ASD symptoms.

Muscle metaboreflex modulation of post‐exercise heart rate kinetics

A delay in the post‐exercise recovery heart rate is a strong predictor of mortality that may be mediated by autonomic nervous system dysfunction (e.g., impaired parasympathetic reactivation and/or augmented sympathetic nerve activity, SNA). We tested the hypothesis that augmented SNA during exercise recovery would delay the rate of post‐exercise heart rate decay compared to a control condition (CTL). Twenty‐two healthy adults (13 f; 22 ± 2 yrs; peak VO2 = 47 ± 7.4 mL/kg/min; BMI = 23.4 kg/m2) performed heavy‐intensity exercise above the ventilatory threshold at 90 ± 6% peak heart rate for 5 min during CTL (no SNA augmentation) and during an experimental (EXP) condition. The EXP condition entailed SNA augmentation via the muscle metaboreflex following 2 min of bilateral isometric handgrip exercise at 30–40% maximal voluntary contraction during cycle ergometry exercise. Bilateral circulatory occlusion was performed during the last 1 min of exercise and continued during 4 min of recovery. Post‐exercise heart rate kinetics were analyzed using paired t‐tests and significant differences were determined when P &lt; 0.05. There was no difference in end‐exercise heart rate (last 1 min) between CTL (159 ± 3 beats/min) and EXP (158 ± 3 beats/min, P = 0.592), amplitude of heart rate recovery between CTL (−61 ± 2 beats/min) and EXP (−64 ± 2 beats/min, P = 0.178), or end recovery heart rate between CTL (98 ± 3 beats/min) and EXP (94 ± 3 beats/min, P = 0.068). There was a significant difference in heart rate kinetics between CTL (57 ± 3 s) and EXP (69 ± 5 s, P = 0.009). These findings suggest that augmented SNA may modulate a delay in the recovery time for heart rate following heavy intensity exercise.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A comparative study on vagal activity in normotensive, pre-hypertensive, and hypertensive individuals

Background: Hypertension is the most common non-communicable disease which on a long term can lead to coronary artery disease and stroke. Pre-hypertension is one step toward hypertension. Pre-hypertension if detected at an earlier stage and intervened, the risk of hypertension and consequently the cardiovascular risk of the individual can be reduced. Vagal tone is an indirect measure of the baroreflex arc integrity. The present study was done to evaluate the vagal (parasympathetic) activity in normotensive (NT), pre-hypertensive (PT), and hypertensive (HT) individuals. Aims and objectives: The aims of this study were to compare the differences in vagal activity in NT, PT, and HT individuals. Materials and Methods: The following parasympathetic function tests were performed on 30 NT, 30 PT, and 30 HT subjects: (1) Heart rate (HR) response to standing, (2) HR response to deep breathing, and (3) Valsalva maneuver. Results: Our findings showed that there is a severely impaired parasympathetic activity in HTs and a mildly impaired parasympathetic activity in PTs. Conclusion: In PTs, non-pharmacological measures like deep breathing exercises and yoga might improve the vagal tone and help in the prevention of hypertension and its complications in future.

Contribution of Impaired Parasympathetic Activity to Right Ventricular Dysfunction and Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

The beneficial effects of parasympathetic stimulation have been reported in left heart failure, but whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in patients with PAH, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition, in experimental pulmonary hypertension (PH). Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction was assessed in 112 patients with PAH. Expression of nicotinic (α-7 nicotinic acetylcholine receptor) and muscarinic (muscarinic acetylcholine type 2 receptor) receptors, and acetylcholinesterase activity were evaluated in RV (n=11) and lungs (n=7) from patients with PAH undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg per day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg subcutaneously) injection followed by 4 weeks of hypoxia. In a subgroup, sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomly assigned to vehicle or treatment (both n=12). At the end of the study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological, and protein analyses. Patients with PAH with lower RV ejection fraction (<41%) had a significantly reduced heart rate recovery in comparison with patients with higher RV ejection fraction. In PAH RV samples, α-7 nicotinic acetylcholine receptor was increased and acetylcholinesterase activity was reduced versus controls. No difference in muscarinic acetylcholine type 2 receptor expression was observed. Chronic PYR treatment in PH rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, and RV α-7 nicotinic acetylcholine receptor and muscarinic acetylcholine type 2 receptor expression, as well. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload, and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation. RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH, with an inadequate adaptive response of the cholinergic system in the RV. Enhancing parasympathetic activity by PYR improved survival, RV function, and pulmonary vascular remodeling in experimental PH.

Autonomic dysfunction determines stress-induced cardiovascular and immune complications in mice.

BackgroundClinical studies suggest that acute inflammation in patients with elevated heart rate (HR) increases morbidity and mortality. The SJL/J (SJL) inbred mouse strain is a unique genetic model that has higher HR and systemic and vascular inflammation compared with C3HeB/FeJ (C3HeB) mice. The goal of this study was to investigate the role of stress on cardiac and vascular complications between 2 strains.Methods and ResultsRadiotelemetry was used for continuous recordings of HR and blood pressure in mice. Hemodynamic differences between mouse strains were very small without stress; however, tail-cuff training generated mild stress and significantly increased HR (≈2-fold) in SJL compared with C3HeB mice. Circulating proinflammatory monocytes (CD11b+Ly6CHi) significantly increased in SJL mice but not in C3HeB mice after stress. Presence of Ly6C+ cells in injured carotids was elevated only in SJL mice after stress; however, a transfer of bone marrow cells from SJL/C3HeB to C3HeB/SJL chimeras had no effect on HR or vascular inflammation following stress. Arterial inflammation (VCAM-1+) was greater in SJL inbred mice or SJL recipient chimeras, even without stress or injury. HR variability was reduced in SJL mice compared with C3HeB mice.ConclusionsWe found that impaired parasympathetic activity is central for stress-induced elevation of HR and systemic and vascular inflammation; however, immune cells from stress-susceptible mice had no effect on HR or vascular inflammation in stress-protected mice.

Decline in serum cholinesterase activities predicts 2-year major adverse cardiac events.

Parasympathetic activity influences long-term outcome in patients with cardiovascular disease, but the underlying mechanism(s) linking parasympathetic activity and the occurrence of major adverse cardiovascular events (MACEs) are incompletely understood. The aim of this pilot study was to evaluate the association between serum cholinesterase activities as parasympathetic biomarkers and the risk for the occurrence of MACEs. Cholinergic status was determined by measuring the cumulative capacity of serum acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) to hydrolyze the AChE substrate acetylthiocholine. Cholinergic status was evaluated in randomly selected patients undergoing cardiac catheterization. The patients were divided into two groups of 100 patients in each group, with or without occurrence of MACEs during a follow-up period of 40 months. Cox regression models adjusted for potential clinical, metabolic and inflammatory confounders served to evaluate association with clinical outcome. We found that patients with MACE presented lower cholinergic status and AChE values at catheterization (1,127 ± 422 and 359 ± 153 nmol substrate hydrolyzed per minute per milliliter, respectively) than no-MACE patients (1,760 ± 546 and 508 ± 183 nmol substrate hydrolyzed per minute per milliliter, p < 0.001 and p < 0.001, respectively), whose levels were comparable to those of matched healthy controls (1,622 ± 303 and 504 ± 126 nmol substrate hydrolyzed per minute per milliliter, respectively). In a multivariate analysis, patients with AChE or total cholinergic status values below median showed conspicuously elevated risk for MACE (hazard ratio 1.85 [95% confidence interval [CI] 1.09-3.15, p = 0.02] and 2.21 [95% CI 1.22-4.00, p = 0.009]) compared with those above median, even after adjusting for potential confounders. We conclude that parasympathetic dysfunction expressed as reduced serum AChE and AChE activities in patients compared to healthy controls can together reflect impaired parasympathetic activity. This impairment predicts the risk of MACE up to 40 months in such patients. Monitoring these parasympathetic parameters might help in the risk stratification of patients with cardiovascular disease.

The Importance of Acute Hypertensive Response in ICH

Acute hypertensive response is the elevation of blood pressure (BP) above normal and premorbid values that initially occurs within the first 24 hours of symptom onset in patients with intracerebral hemorrhage (ICH).1 The acute hypertensive response is characterized by its high prevalence, self-limiting nature, and prognostic significance. To remain consistent with the 2003 World Health Organization/International Society of Hypertension statement,2 acute hypertensive response is defined as systolic BP (SBP)≥140 mm Hg demonstrated on 2 recordings taken 5 minutes apart within 24 hours of symptom onset. A total of 33 992 patients (75.0%) had an initial SBP≥140 mm Hg among 45 330 patients presenting with an ICH analyzed in the National Hospital Ambulatory Medical Care Survey.3 Acute hypertensive response is usually set on the platform of inadequately treated or undetected chronic hypertension. However, elevation and spontaneous reduction in the initial BP during the next few days support the role of other transient and stroke-specific mechanisms. Presumably, the primary cause of the acute hypertensive response is damage or compression of specific regions in the brain that mediate autonomic control with functional adaptation during the next few days.4,5 Hypertensive responses to other factors are exaggerated and additive because of impaired parasympathetic activity and baroreceptor sensitivity.6 This article addresses the state of knowledge about acute therapy for hypertensive response with ICH. The treatment of acute hypertensive response in ICH has been controversial for the past 3 decades. The Figure demonstrates the 4 periods of evolution in our understanding of pathophysiology and treatment. The current notion of treatment is based on the observation that one third of the subjects presenting with ICH demonstrate hematoma expansion (with subsequent deterioration and death) in the first few hours after onset.7 An initial SBP of ≥200 mm Hg is associated with …

The vagus nerve and autonomic imbalance in heart failure: past, present, and future

Advances in heart failure (HF) therapeutics over the last 20 years have led to widespread acceptance and use of oral antagonists of the renin–angiotensin–aldosterone (RAAS) and sympathetic nervous (SNS) systems [1, 2] in patients with a depressed ejection fraction. In addition, implantable cardioverter defibrillators and cardiac resynchronization devices (CRT) have been widely adopted in both practice guidelines and clinical care [3–5]. Nevertheless, with the aging of the population and rising disease prevalence, interest in the development of newer approaches has continued, and several are now under investigation [6, 7]. The need for novel paradigms is further highlighted by the fact that intensification of antagonism of the RAAS has not been shown to reduce mortality [8–10], and other pharmacologic and device approaches including anticytokine therapy, epicardial constraining devices, and novel stimulation technologies have not been convincingly associated with improvements in hard clinical outcomes [11–13]. There are also multiple clinical scenarios that suggest areas of unmet need in HF such as CRT non-responders and patients who are not candidates for CRT due to narrow complex QRS morphologies [14, 15]. Thus, there continues to be a need for innovative therapies for patients with heart failure. One area of recent focus in heart failure research has been the role of autonomic imbalance. In particular, there is increasing evidence that in addition to increased sympathetic activation, parasympathetic withdrawal may also contribute to the pathogenesis of heart failure [16]. However, while beta-blockade has found its place as a leading disease modifying therapy that impacts the sympathetic nervous system, far less is known about methods to augment parasympathetic function. In this context, the topics of vagus nerve anatomy, physiology and influence on cardiac function are reviewed in detail in the current issue of Heart Failure Reviews. These papers form a foundation for understanding the clinical potential of a new intervention, vagus nerve stimulation (VNS). Pre-clinical data (including models of acute ischemia and chronic failure) and phase II experience in Europe with VNS are reviewed as are other potential ways to influence vagus nerve function. The current issue begins with a historical overview of experimental physiologic and clinical-translational work performed by Dr. Peter Schwartz and colleagues, on parasympathetic–sympathetic interactions in both ischemic heart disease and heart failure [17]. Drs. Chapleau and Sabharwal provide a highly detailed review of the concepts of cardiovagal tone, parasympathetic modulation, parasympathetic re-activation, and reflex changes in heart rate and the methods used to assess them [18]. Normal vagus nerve anatomy is described in an elegant paper by Bibevski and Dunlap, who discuss the multitude of potential sites that might contribute to impaired parasympathetic nerve activity and offer evidence that points to specific locations of the defects, including the post-ganglionic nicotinic acetylcholine receptor [19]. The potential mechanisms that mediate the effects of VNS in heart failure are discussed by Li and Olshansky, who review the influence of efferent and P. J. Hauptman Department of Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA

Autonomic effects on QT-RR interval dynamics after exercise

This study was designed to assess autonomic effects on the QT interval during recovery from exercise. Exercise is associated with an acute increased risk of sudden cardiac death. Evidence of impaired parasympathetic activity, such as low heart rate variability and heart rate recovery, and an increased QT interval are also associated with increased mortality. However, there is no clear pathophysiological link among these findings. Bicycle exercise testing was performed serially in 33 healthy volunteers (19 men; ages, 54 +/- 7 yr) under four conditions: 1) baseline, 2) beta-adrenergic blockade-intravenous propranolol (0.2 mg/kg) administered during exercise, 3) parasympathetic blockade-intravenous atropine (0.04 mg/kg) administered during exercise, and 4) double blockade with propranolol and atropine. ECGs were obtained every minute in recovery for 10 min and then at the 15th and 20th min, from which the QT and RR intervals were measured. Linear regression analyses were used to assess the individual QT-RR relationships for each subject for each condition. Relative to baseline, the QT-RR relationship with parasympathetic blockade was shifted to the left and had a steeper slope. In contrast, the QT-RR relationship with beta-adrenergic blockade was shifted to the right and had a less steep slope. The baseline and double-blockade QT-RR relationships were in the middle and essentially superimposable. There was a negative relationship between QT-RR slope and heart rate or RR interval recoveries, but it was significant only for the 1- and 2-min RR interval recoveries with low R(2) values of 0.124 and 0.114. The main parasympathetic effect in the postexercise recovery period is to counteract the sympathetically mediated QT prolongation. These data support the concept that parasympathetic tone may provide a natural antiarrhythmic effect during this time.

Association between cardiovascular autonomic neuropathy and left ventricular hypertrophy in diabetic haemodialysis patients.

Patients with diabetic nephropathy are likely to have neurological complications including cardiovascular autonomic dysfunction, which is related to increased risk of mortality. We investigated whether cardiovascular autonomic neuropathy is associated with left ventricular hypertrophy (LVH) in diabetic haemodialysis patients. Holter electrocardiography was carried out for 24 h with time and frequency domain analyses of heart rate variability in 154 diabetic (age 62+/-11 years) and 63 non-diabetic haemodialysis patients (62+/-10 years). The left ventricular mass index (LVMI) was determined by echocardiography. We used the percentage of differences exceeding 50 ms between adjacent normal RR intervals (pNN50) in time domain analysis and the power in the high-frequency range (HF: 0.15-0.40 Hz) in frequency domain analysis as indicators of parasympathetic activity. The mean LVMI was greater in diabetic than in non-diabetic patients (168+/-63 vs 144+/-54 g/m(2), P<0.01). LVMI inversely correlated with pNN50 (r = -0.270, P = 0.0007, n = 154) and HF (r = -0.277, P = 0.0005, n = 154) in diabetic patients, but not in non-diabetic patients. By multiple logistic analysis, LVH was strongly associated with pNN50 (odds ratio 0.088; 0, <2%; 1, >/=2%) and HF (odds ratio 0.058; 0, <500 ms(2); 1, >/=500 ms(2)) in diabetic patients. Impaired parasympathetic activity, which indicates cardiovascular autonomic neuropathy, was associated with the presence of LVH in diabetic haemodialysis patients. The co-existence of cardiovascular autonomic neuropathy and LVH may be one of the key factors for the high incidence of cardiovascular events in diabetic haemodialysis patients.