BackgroundAbnormal cardiac innervation plays an important role in arrhythmogenicity after myocardial infarction (MI). Data regarding reperfusion models and innervation abnormalities in the medium... Show moreBackgroundAbnormal cardiac innervation plays an important role in arrhythmogenicity after myocardial infarction (MI). Data regarding reperfusion models and innervation abnormalities in the medium to long term after MI are sparse. Histologic quantification of the small-sized cardiac nerves is challenging, and transmural analysis has not been performed.ObjectivesThis study sought to assess cardiac innervation patterns in transmural biopsy sections in a porcine reperfusion model of MI (MI-R) using a novel method for nerve quantification.MethodsTransmural biopsy sections from 4 swine (n = 83) at 3 months after MI-R and 3 controls (n = 38) were stained with picrosirius red (fibrosis) and beta-III-tubulin (autonomic nerves). Biopsy sections were classified as infarct core, border zone, or remote zone. Each biopsy section was analyzed with a custom software pipeline, allowing calculation of nerve density and classification into innervation types at the 1 × 1–mm resolution level. Relocation of the classified squares to the original biopsy position enabled transmural quantification and innervation heterogeneity assessment.ResultsCoexisting hyperinnervation, hypoinnervation, and denervation were present in all transmural MI-R biopsy sections. The innervation heterogeneity was greatest in the infarct core (median: 0.14; IQR: 0.12-0.15), followed by the border zone (median: 0.05; IQR: 0.04-0.07; P = 0.02) and remote zone (median: 0.02; IQR: 0.02-0.03; P < 0.0001). Only in the border zone was a positive linear relation between fibrosis and innervation heterogeneity observed (R = 0.79; P < 0.0001).ConclusionsThis novel method allows quantification of nerve density and heterogeneity in large transmural biopsy sections. In the chronic phase after MI-R, alternating innervation patterns were identified within the same biopsy section. Persistent innervation heterogeneity, in particular in the border zone biopsy sections, may contribute to late arrhythmogenicity. Show less
Gerritsen, R.J.S.; Band, G.P.H.; Lafeber, J.; van den Beukel, N.; van Voskuilen, B.; Hoogland, R. 2023
Background and purposeThe objective was to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on European clinical autonomic practice.MethodsEighty-four neurology-driven or... Show moreBackground and purposeThe objective was to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on European clinical autonomic practice.MethodsEighty-four neurology-driven or interdisciplinary autonomic centers in 22 European countries were invited to fill in a web-based survey between September and November 2021.ResultsForty-six centers completed the survey (55%). During the first pandemic year, the number of performed tilt-table tests, autonomic outpatient and inpatient visits decreased respectively by 50%, 45% and 53%, and every third center reported major adverse events due to postponed examinations or visits. The most frequent newly diagnosed or worsened cardiovascular autonomic disorders after COVID-19 infection included postural orthostatic tachycardia syndrome, orthostatic hypotension and recurrent vasovagal syncope, deemed to be likely related to the infection by ≥50% of the responders. Forty-seven percent of the responders also reported about people with new onset of orthostatic intolerance but negative tilt-table findings, and 16% about people with psychogenic pseudosyncope after COVID-19. Most patients were treated non-pharmacologically and symptomatic recovery at follow-up was observed in ≥45% of cases. By contrast, low frequencies of newly diagnosed cardiovascular autonomic disorders following COVID-19 vaccination were reported, most frequently postural orthostatic tachycardia syndrome and recurrent vasovagal syncope, and most of the responders judged a causal association unlikely. Non-pharmacological measures were the preferred treatment choice, with 50%–100% recovery rates at follow-up.ConclusionsCardiovascular autonomic disorders may develop or worsen following a COVID-19 infection, whilst the association with COVID-19 vaccines remains controversial. Despite the severe pandemic impact on European clinical autonomic practice, a specialized diagnostic work-up was pivotal to identify non-autonomic disorders in people with post-COVID-19 orthostatic complaints. Show less
BACKGROUND Nonischemic cardiomyopathy patients referred for catheter ablation of ventricular arrhythmias (VAs) typically have either inferolateral (ILS) or anteroseptal (ASS) VA substrate locations... Show moreBACKGROUND Nonischemic cardiomyopathy patients referred for catheter ablation of ventricular arrhythmias (VAs) typically have either inferolateral (ILS) or anteroseptal (ASS) VA substrate locations, with poorer outcomes for ASS. Sympathetic denervation is an important determinant of arrhythmogenicity. Its relation to nonischemic fibrosis in general and to the different VA substrates is unknown.OBJECTIVES This study sought to evaluate the association between VA substrates, myocardial fibrosis, and sympa-thetic denervation. METHODS Thirty-five patients from the Leiden Nonischemic Cardiomyopathy Study, who underwent electroanatomic voltage mapping and iodine-123 metaiodobenzylguanidine imaging between 2011 and 2018 were included. Late gadolinium-enhanced cardiac magnetic resonance data were collected when available. The relation between global cardiac sympathetic innervation and area-weighted unipolar voltage (UV) as a surrogate for diffuse fibrosis was evalu-ated. For regional analysis, patients were categorized as ASS or ILS. The distribution of low UV, sympathetic denervation, and late gadolinium enhancement (LGE) scar were compared using the 17-segment model.RESULTS Median area-weighted UV was 12.3 mV in patients with normal sympathetic innervation and 8.7 mV in patients with sympathetic denervation. Global sympathetic denervation correlated with diffuse myocardial fibrosis (R = 0.53; P = 0.02). ILS (n = 13) matched with low UV, sympathetic denervation, and LGE scar in all patients, whereas ASS (n = 11) matched with low UV in all patients, with LGE scar in 63% (P = 0.20), but with sympathetic denervation in only 27% of patients (P = 0.0002).CONCLUSIONS Global cardiac sympathetic denervation is related to fibrosis in nonischemic cardiomyopathy patients with VA. The mismatch between regional fibrosis and preserved innervation for ASS may contribute to a VA substrate difficult to control by catheter ablation. (J Am Coll Cardiol EP 2022;8:1234-1245)(c) 2022 by the American College of Cardiology Foundation. Show less
BACKGROUND: Cardioinhibition may diminish with age, but the changing balance of cardioinhibition and vasodepression with age has not been quantified, leaving the mechanism of vasovagal syncope (VVS... Show moreBACKGROUND: Cardioinhibition may diminish with age, but the changing balance of cardioinhibition and vasodepression with age has not been quantified, leaving the mechanism of vasovagal syncope (VVS) in old age unclear .OBJECTIVES: This study sought to quantify age-related changes of vasodepression and cardioinhibition in tilt-induced VVS. METHODS: We studied 163 cases of tilt-induced WS, evoked using the Italian protocol with blood pressure, heart rate, and video-etectroencephalographic monitoring. Presyncope was excluded. Cardioinhibition was defined as the heart rate decrease before syncope; asystotic pauses (>= 3 seconds) were divided into early and late asystole, ie, beginning early enough to or too late to be the major cause of toss of consciousness. The log-ratio method was used to quantify contributions of cardioinhibition and vasodepression, assessed in 2 10-second periods before the onset of cardioinhibition and before syncope. RESULTS: With increasing age, cardioinhibition decreased, ie, heart rate decreased less and more slowly near syncope (P < 0.0001), white vasodepression increased. Asystotic pauses were less frequent in the older one-half of the group than the younger one-half (26% vs 57%; P < 0.00001), but when it did, late asystole occurred more often (58% vs 15%; P < 0.001). CONCLUSIONS: The shift toward less cardioinhibition and more vasodepression with increased age probably reflects a physiological shift in circulatory control. The weakening of cardioinhibition with age may detract from the efficacy of pacing in older patients with VVS. Cardioinhibition-vasodepression balance should be considered in pacing decisions in older subjects with VVS. (C) 2022 by the American College of Cardiology Foundation. Show less
Introduction In patients with ictal asystole (IA) both cardioinhibition and vasodepression may contribute to syncopal loss of consciousness. We investigated the temporal relationship between onset... Show moreIntroduction In patients with ictal asystole (IA) both cardioinhibition and vasodepression may contribute to syncopal loss of consciousness. We investigated the temporal relationship between onset of asystole and development of syncope in IA, to estimate the frequency with which pacemaker therapy, by preventing severe bradycardia, may diminish syncope risk. Methods In this retrospective cohort study, we searched video-EEG databases for individuals with focal seizures and IA (asystole >= 3 s preceded by heart rate deceleration) and assessed the durations of asystole and syncope and their temporal relationship. Syncope was evaluated using both video observations (loss of muscle tone) and EEG (generalized slowing/flattening). We assumed that asystole starting <= 3 s before syncope onset, or after syncope began, could not have been the dominant cause. Results We identified 38 seizures with IA from 29 individuals (17 males; median age: 41 years). Syncope occurred in 22/38 seizures with IA and was more frequent in those with longer IA duration (median duration: 20 [range: 5-32] vs. 5 [range: 3-9] s; p < .001) and those with the patient seated vs. supine (79% vs. 46%; p = .049). IA onset always preceded syncope. In 20/22 seizures (91%), IA preceded syncope by >3 s. Thus, in only two instances was vasodepression rather than cardioinhibition the dominant presumptive syncope triggering mechanism. Conclusions In IA, cardioinhibition played an important role in most seizure-induced syncopal events, thereby favoring the potential utility of pacemaker implantation in patients with difficult to suppress IA. Show less
The cardiac autonomic nervous system (cANS) regulates cardiac adaptation to different demands. The heart is an asymmetrical organ, and in the selection of adequate treatment of cardiac diseases it... Show moreThe cardiac autonomic nervous system (cANS) regulates cardiac adaptation to different demands. The heart is an asymmetrical organ, and in the selection of adequate treatment of cardiac diseases it may be relevant to take into account that the cANS also has sidedness as well as regional differences in anatomical, functional, and molecular characteristics. The left and right ventricles respond differently to adrenergic stimulation. Isoforms of nitric oxide synthase, which plays an important role in parasympathetic function, are also distributed asymmetrically across the heart. Treatment of cardiac disease heavily relies on affecting left-sided heart targets which are thought to apply to the right ventricle as well. Functional studies of the right ventricle have often been neglected. In addition, many principles have only been investigated in animals and not in humans. Anatomical and functional heterogeneity of the cANS in human tissue or subjects is highly valuable for understanding left- and right-sided cardiac pathology and for identifying novel treatment targets and modalities. Within this perspective, we aim to provide an overview and synthesis of anatomical and functional heterogeneity of the cANS in tissue or subjects, focusing on the human heart. Show less
BackgroundDespite the increasing interest in cardiac autonomic nervous activity, the normal development is not fully understood. The main aim was to determine the maturation of different cardiac... Show moreBackgroundDespite the increasing interest in cardiac autonomic nervous activity, the normal development is not fully understood. The main aim was to determine the maturation of different cardiac sympathetic-(SNS) and parasympathetic nervous system (PNS) activity parameters in healthy patients aged 0.5 to 20 years. A second aim was to determine potential sex differences.Methods and ResultsFive studies covering the 0.5- to 20-year age range provided impedance- and electrocardiography recordings from which heart rate, different PNS-parameters (eg, respiratory sinus arrhythmia) and an SNS-parameter (pre-ejection period) were collected. Age trends were computed in the mean values across 12 age-bins and in the age-specific variances. Age was associated with changes in mean and variance of all parameters. PNS-activity followed a cubic trend, with an exponential increase from infancy, a plateau phase during middle childhood, followed by a decrease to adolescence. SNS-activity showed a more linear trend, with a gradual decrease from infancy to adolescence. Boys had higher SNS-activity at ages 11 to 15 years, while PNS-activity was higher at 5 and 11 to 12 years with the plateau level reached earlier in girls. Interindividual variation was high at all ages. Variance was reasonably stable for SNS- and the log-transformed PNS-parameters.ConclusionsCardiac PNS- and SNS-activity in childhood follows different maturational trajectories. Whereas PNS-activity shows a cubic trend with a plateau phase during middle childhood, SNS-activity shows a linear decrease from 0.5 to 20 years. Despite the large samples used, clinical use of the sex-specific centile and percentile normative values is modest in view of the large individual differences, even within narrow age bands. Show less
Rationale: Assessing the relative contributions of cardioinhibition and vasodepression to the blood pressure (BP) decrease in tilt-induced vasovagal syncope requires methods that reflect BP... Show moreRationale: Assessing the relative contributions of cardioinhibition and vasodepression to the blood pressure (BP) decrease in tilt-induced vasovagal syncope requires methods that reflect BP physiology accurately. Objective: To assess the relative contributions of cardioinhibition and vasodepression to tilt-induced vasovagal syncope using novel methods. Methods and Results: We studied the parameters determining BP, that is, stroke volume (SV), heart rate (HR), and total peripheral resistance (TPR), in 163 patients with tilt-induced vasovagal syncope documented by continuous ECG and video EEG monitoring. We defined the beginning of cardioinhibition as the start of an HR decrease (HR) before syncope and used logarithms of SV, HR, and TPR ratios to quantify the multiplicative relation BP=SV center dot HR center dot TPR. We defined 3 stages before syncope and 2 after it based on direction changes of these parameters. The earliest BP decrease occurred 9 minutes before syncope. Cardioinhibition was observed in 91% of patients at a median time of 58 seconds before syncope. At that time, SV had a strong negative effect on BP, TPR a lesser negative effect, while HR had increased (allP<0.001). At the onset of cardioinhibition, the median HR was at 98 bpm higher than baseline. Cardioinhibition thus initially only represented a reduction of the corrective HR increase but was nonetheless accompanied by an immediate acceleration of the ongoing BP decrease. At syncope, SV and HR contributed similarly to the BP decrease (P<0.001), while TPR did not affect BP. Conclusions: The novel methods allowed the relative effects of SV, HR, and TPR on BP to be assessed separately, although all act together. The 2 major factors lowering BP in tilt-induced vasovagal syncope were reduced SV and cardioinhibition. We suggest that the term vasodepression in reflex syncope should not be limited to reduced arterial vasoconstriction, reflected in TPR, but should also encompass venous pooling, reflected in SV. Show less
Heart rate variability (HRV) is a non-invasive indicator of autonomic nervous system function. HRV recordings show artefacts due to technical and/or biological issues. The Kubios software is one of... Show moreHeart rate variability (HRV) is a non-invasive indicator of autonomic nervous system function. HRV recordings show artefacts due to technical and/or biological issues. The Kubios software is one of the most used software to process HRV recordings, offering different levels of threshold-based artefact correction (i.e., Kubios filters). The aim of the study was to analyze the impact of different Kubios filters on the quantification of HRV derived parameters from short-term recordings in three independent human cohorts. A total of 312 participants were included: 107 children with overweight/obesity (10.0 +/- 1.1 years, 58% men), 132 young adults (22.2 +/- 2.2 years, 33% men) and 73 middle-aged adults (53.6 +/- 5.2 years, 48% men). HRV was assessed using a heart rate monitor during 10-15 min, and the Kubios software was used for HRV data processing using all the Kubios filters available (i.e., 6). Repeated-measures analysis of variance indicated significant differences in HRV derived parameters in the time-domain (all p < 0.001) across the Kubios filters in all cohorts, moreover similar results were observed in the frequency-domain. When comparing two extreme Kubios filters, these statistical differences could be clinically relevant, e.g. more than 10 ms in the standard deviation of all normal R-R intervals (SDNN). In conclusion, the results of the present study suggest that the application of different Kubios filters had a significant impact on HRV derived parameters obtained from short-term recordings in both time and frequency-domains. Show less
Ruigh, E.L. de; Jansen, L.M.C.; Vermeiren, R.; Popma, A. 2019
In order to gain insight in empathic deficits in juveniles with severe antisocial problems and psychopathic traits, self-reported psychopathic traits and trait empathy were assessed in 416 detained... Show moreIn order to gain insight in empathic deficits in juveniles with severe antisocial problems and psychopathic traits, self-reported psychopathic traits and trait empathy were assessed in 416 detained male juveniles. State empathy was assessed by self-reported empathic and autonomic nervous system (ANS) responses to sad film clips. Psychopathic traits were significantly negatively correlated with empathy, although not with ANS responses. Individuals reporting no empathy showed significantly less heart rate withdrawal compared to individuals reporting higher empathy. This implies that physiological responses may be helpful in identifying juveniles with severely impaired empathic functioning, even in a severely antisocial sample. Show less