Skip to main content
Download PDF

Cardiac autonomic dysfunction in adult congenital heart disease

BMC Cardiovascular Disorders volume 23, Article number: 513 (2023) Cite this article

Abstract

Purpose

Due to recent advances in diagnosis and treatment, the number of adults with congenital heart disease (ACHD) has substantially increased. This achievement is mitigated by rhythm disorders. Here, we sought to determine alterations in heart rate variability (HRV) and their prognostic value in ACHD.

Methods

Ninety seven ACHD patients (39.2 ± 14.1 years, 51.5% female) and 19 controls (39.7 ± 15.0 years, 47.4% female) underwent 24-h Holter monitoring.

Results

As compared to controls, ACHD patients offered a significantly higher burden of premature ventricular contractions (p = 0.02) and decreased HRV indices (natural logarithmic transformation of very low frequency (lnVLF): 7.46 ± 0.76 ms2 vs. 7.91 ± 0.92ms2, p = 0.03; natural logarithmic transformation of low frequency (lnLF): 6.39 ± 0.95ms2 vs. 7.01 ± 1.07ms2, p = 0.01; natural logarithmic transformation of the ratio of low to high frequency spectra (lnLF/HF): 0.81 ± 0.74 vs. 1.17 ± 0.51, p = 0.04). No differences in HRV measures were observed across ACHD lesion groups. NT-proBNP levels were significantly related to both time and frequency domain indices (natural logarithmic transformation of the standard deviation of NN intervals (lnSDNN): Spearman´s rho = -0.32, p = 0.001; natural logarithmic transformation of the standard deviation of the average NN intervals for each 5-min segment of a 24-h Holter monitoring (lnSDANN): Spearman´s rho: -0.33, p = 0.001; natural logarithmic transformation of the total power (lnTP): Spearman´s rho: -0.25, p = 0.01; lnVLF: Spearman´s rho: -0.33, p = 0.001; lnLF: Spearman´s rho: -0.35, p < 0.001; lnLF/HF: Spearman´s rho: -0.34, p = 0.001).

After a mean follow-up of 3.9 ± 0.7 years, 8 patients died and 3 patients survived sudden cardiac death (SCD). Several HRV parameters were significantly higher in event-free ACHD patients than in those who died or survived SCD (natural logarithmic transformation of the average of the standard deviations of NN intervals for each 5-min segment of a 24-h Holter monitoring (lnASDNN): p = 0.04; lnPNN30: p = 0.04; lnVFL: p = 0.03; lnLF: p < 0.01). On univariate Cox regression analysis, the time domain indices lnSDNN, lnASDNN and lnPNN30, as well as the frequency domain parameters lnTP, lnVLF and lnLF were associated with death and survived cardiac arrest.

Conclusion

ACHD is accompanied by HRV impairment that carries prognostic implications on ACHD mortality and survived SCD.

Peer Review reports

Introduction

Congenital heart disease with an approximate prevalence of 9 per 1000 new-borns worldwide is a common inborn defect which used to carry a very poor prognosis. However, due to advancements in diagnosis and management, > 90% of these patients reach adulthood nowadays [1]. This has led to a growing population of adults with congenital heart disease (ACHD). Despite medical advances, ACHD patients are afflicted by long-term complications including arrhythmias. They encompass the whole range of atrial and junctional tachycardias, bradyarrhythmias and ventricular arrhythmias which are a major cause of hospitalization and mortality [2]. In the ACHD population, sudden cardiac death (SCD) constitutes up to 40% of all deaths. In keeping with this, management of arrhythmias is an essential compound of ACHD care.

The autonomic nervous system plays an important role in the modulation of cardiac electrophysiology and arrhythmogenesis. Cardiac autonomic nervous dysfunction is associated with the occurrence of malignant arrhythmias and an increased risk of death in acquired cardiac diseases. Autonomic dysfunction is also common in patients with ACHD [3, 4] and small studies already suggested that it could be a means of risk assessment in this population [5]. Measurement of heart rate variability (HRV) represents a non-invasive approach to evaluate alterations in cardiac autonomic function [6]. HRV describes the fluctuations of normal heart beat intervals during electrocardiography (ECG)-monitoring. Decreased HRV is a strong predictor of adverse prognosis. HRV reduction has been shown to have prognostic implications in coronary heart disease, especially in the early post-myocardial infarction period [7]. In acquired heart failure, reduced HRV has been identified as an independent predictor of ventricular arrhythmias, SCD and mortality [8]. However, in the population of ACHD patients, its diagnostic and prognostic value remains less well defined.

Thus, the aim of this prospective cohort study was i) to identify alterations in HRV in ACHD patients as a function of the underlying congenital lesion, ii) to compare the results with those obtained in healthy controls and iii) to assess the prognostic value of HRV measurements for risk stratification in ACHD patients.

Material and methods

Study population

Between January 2018 and January 2020, ACHD patients aged ≥ 18 years were screened for this prospective cohort trial. All patients received treatment at the Department of Cardiology, Hospital of Bonn (Bonn, Germany). Patients with an implanted cardiac pacemaker were excluded from study participation. In line with the current guidelines on ACHD management [9], patients were classified into four lesion groups namely a) shunt lesions, b) left-sided obstructive lesions, c) right-sided lesions and d) complex lesions.

Healthy controls without preexisting structural cardiac disease were recruited by screening invitation from the general population and were matched for age and gender. Both ACHD patients and controls underwent a standardized questionnaire-based clinical evaluation, 24-h Holter monitoring, transthoracic echocardiography and laboratory testing. Written informed consent was obtained from each participant. The study was performed in line with the principles of the 1975 Declaration of Helsinki. Approval was obtained from the Medical Ethics Committee of the University of Bonn (Germany).

The study´s primary objective was to analyse the frequency and impact of altered HRV in ACHD patients. Its primary outcome was the composite of death or survived cardiac arrest during follow-up in ACHD.

Holter monitoring

Holter monitoring was carried out on a five lead 24-h ECG (SpiderView, MicroPort CRM, Paris, France). Holter recordings were manually analysed by a cardiologist who discarded artefacts and edited misclassified heartbeats. All ECG data were examined for presence of arrhythmic events comprising premature atrial and ventricular contractions (PAC and PVC, respectively), as well as supraventricular and ventricular salvos and tachyarrhythmias.

HRV analyses were performed by use of SyneScope Version 3.10 software (MicroPort CRM, Paris, France) and comprehended both time and frequency domain measures. For time domain analysis, normal-to-normal (NN) sinus interbeat intervals were evaluated, resulting in the following measures: 1.) standard deviation of NN intervals (SDNN); 2.) standard deviation of the average NN intervals for each 5-min segment of a 24-h ECG recording (SDANN); 3.) average of the standard deviations of NN intervals for each 5-min segment of a 24-h ECG recording (ASDNN); 4.) root mean square of differences between NN intervals (RMSSD); 5.) percentage of NN intervals that differ from the prior interval by at least 30 ms or 50 ms (PNN30 and PNN50, respectively). Frequency domain HRV analysis was conducted by spectral analysis based on fast Fourier transform. The following frequency bands were obtained: 1.) very low frequency (VLF) spectrum (0.0033–0.04 Hz) that is generated by the stimulation of afferent sensory neurons in the heart and modulated by physical activity and stress response; 2.) low frequency (LF) spectrum (0.04–0.15 Hz) that reflects both vagal and sympathetic influences; 3.) high frequency (HF) spectrum (0.15–0.40 Hz) that represents parasympathetic activity; 4.) the ratio of low to high frequency spectra (LF/HF ratio) that estimates the ratio between sympathetic to parasympathetic nervous system activity; 5.) total power (TP) spectrum (≤ 0.40 Hz) that sums up the aforementioned spectra and captures the total variance in HRV. Due to the skewed, not normal distribution of time and frequency domain variables, a natural logarithmic transformation (ln) was applied for all HRV measurements.

Transthoracic echocardiography

A complete transthoracic echocardiographic study was performed by experienced cardiac sonographers trained in the field of ACHD according to current guidelines [10]. Ultrasound data were acquired with a 2.5 MHz phased-array transducer using a commercially available ultrasound system (iE33, Philips Medical Systems, Andover, Massachusetts; GE Vivid E9, GE Health Medical, Horten, Norway). Systolic ventricular function was assessed by biplane Simpson´s method from volumes obtained by the summation of a stack of elliptical discs. In case of a morphologic right systemic ventricle, ventricular function was quantified by cardiac magnetic resonance.

Laboratory testing

The study participants underwent blood sampling. Measurements encompassed a complete blood cell count, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), serum creatinine and thyroid stimulating hormone (TSH) levels.

Statistical analysis

Continuous variables are presented as mean ± standard deviation, if normally distributed, or as median and interquartile range (IQR, quartile 1/quartile 3), if not normally distributed. HRV indices underwent logarithmic transformation. Continuous variables were tested for having a normal distribution with the use of the Kolmogorov–Smirnov test. Categorical variables are given as absolute numbers and percentages. Comparison across the four ACHD lesion groups of continuous variables was carried out by univariate ANOVA or Kruskal–Wallis H test (if normality assumption was violated). Differences in categorical variables were analysed by Fisher´s exact test. Comparison between the total patient cohort and controls was performed by Student´s t-test or Mann–Whitney U test (if normality assumption was violated). If the global test was significant, Bonferroni correction was applied for post hoc analysis. Spearman’s correlation coefficients were used to establish associations. To assess the relationship between variables and mortality, a univariate Cox proportional hazard regression analysis was performed. Multivariate Cox regression analysis was intended in case of a sufficient number of events per variable. Statistical significance was assumed when the null hypothesis could be rejected at p < 0.05. Statistical analyses were conducted with SPSS Statistics version 26.0 (IBM, Armonk, NY, USA).

Results

Clinical characteristics

A total of 102 ACHD patients were screened for this prospective cohort trial. Five patients were excluded due to incomplete Holter monitoring data, resulting in a final ACHD study population size of 97 participants.

Table 1 summarizes the demographic and clinical features of study participants. Overall, patients were middle-aged (39.2 ± 14.1 years); the gender ratio was largely balanced (51.5% female). As to New York Heart Association (NYHA) functional class, the vast majority was asymptomatic or oligosymptomatic. The systolic function of the systemic ventricle was predominantly preserved with a mean ejection fraction (EF) of 58.3 ± 8.7%. 33 out of 97 patients (34.0%) had a history of arrhythmias, mainly supraventricular in nature; only two patients had a history of non-sustained ventricular tachycardia. 10.3% of ACHD patients were under antiarrhythmic medication. As aforesaid, ACHD patients were categorized into four lesion groups according to their haemodynamics. 26/97 patients (26.8%) had shunt lesions, 21/97 patients (21.6%) presented left-sided obstructive lesions, 28/97 patients (28.9%) offered right-sided lesions; the remaining 22/97 patients (22.6%) had complex lesions. An overview of the underlying defects and prior corrective repair is given in Table 2. ACHD patients were compared to 19 controls without preexisting structural cardiac disease, though three controls were on beta-blockers due to arterial hypertension. When ACHD patients were compared to controls, patients offered a significantly impaired EF (58.3 ± 8.7% vs. 64.0 ± 4.2%; p < 0.01) and higher NT-proBNP levels (140 pg/ml (IQR 60–333) vs. 47 pg/ml (IQR 33–82); p < 0.001). Likewise, after introduction of established NT-proBNP cut-offs at 125 pg/ml and 300 pg/ml, significant differences between ACHD patients and controls could be upheld [11].

Table 1 Baseline characteristics of the study population
Full size table
Table 2 Overview of specific underlying defects and previous corrective repair
Full size table

Holter monitoring

Arrhythmic events over 24 h are displayed in Table 3. The number of study participants that presented PVCs was significantly higher in the patient group than amongst controls (77.3% vs. 52.6%, p = 0.02). However, there were no differences between both groups in terms of PAC, supraventricular or ventricular tachyarrhythmias. When arrhythmic events were compared over ACHD patient groups, only PVC counts varied significantly. Bonferroni adjustment ascribed this effect to differences between the right-sided lesion group, on the one hand, and the shunt and left-sided obstructive lesion group, on the other hand (p = 0.004 and p = 0.04, respectively).

Table 3 Arrhythmic events during Holter monitoring
Full size table

HRV results are given in Table 4. Mean heart rate did not differ between patients and controls (71.0 ± 9.8/min vs. 68.1 ± 11.0/min, p = 0.24) nor over ACHD lesion groups (p = 0.66). In terms of frequency domain analysis, lnVLF (7.46 ± 0.76 ms2 vs. 7.91 ± 0.92ms2; p = 0.03), lnLF (6.39 ± 0.95ms2 vs. 7.01 ± 1.07ms2; p = 0.01) and lnLF/HF (0.81 ± 0.74 vs. 1.17 ± 0.51; p = 0.04) were significant lower in the patient than in the control cohort. With regard to time domain measures, no substantial differences were observed between patients and controls. When HRV measurements were examined over ACHD lesion groups, neither time nor frequency domain analysis showed significant differences in any of the studied parameters. Neither time nor frequency domain HRV parameters were significantly impacted by medication (in particular beta-blocker) or prior surgical intervention of the underlying cardiac defect. Correlation analysis revealed that NT-proBNP levels were significantly related to both time and frequency domain indices (lnSDNN: Spearman´s rho = -0.32, p = 0.001; lnSDANN: Spearman´s rho: -0.33, p = 0.001; lnTP: Spearman´s rho: -0.25, p = 0.01; lnVLF: Spearman´s rho: -0.33, p = 0.001; lnLF: Spearman´s rho: -0.35, p < 0.001; lnLF/HF: Spearman's rho: -0.34, p = 0.001).

Table 4 Heart rate variability measurements
Full size table

Clinical outcomes

During a mean follow-up of 3.9 ± 0.7 years, 8 patients died. The causes of death comprised arrhythmia (n = 1), SCD (n = 4) and heart failure (n = 3). SCD due to ventricular fibrillation occurred in 3 patients who were successfully resuscitated and thereafter underwent implantation of implantable cardioverter-defibrillator for secondary prevention. Almost one in three ACHD patients were hospitalized for at least one time during follow-up (n = 31, 32.0%). 27 (27.8%) patients had at least one event of acute cardiac decompensation during follow-up. These events comprised acute decompensated heart failure due to fluid retention requiring medical therapy optimization that was not necessarily accompanied by hospital admission. On Cox regression analysis, only the time domain indices lnSDANN and lnRMSSD were associated with acute cardiac decompensation. With regard to hospital admission, only lnSDANN showed an association.

To analyse the impact of HRV parameters on patients’ event-free survival, a survival analysis by using a univariate Cox regression analysis was conducted. Although the group of deceased ACHD patients and SCD survivors had higher NT-proBNP levels (333 pg/ml (IQR 90–2492) vs. 135 pg/ml (IQR 54–316)) and decreased EF (48.0 ± 12.4% vs. 58.9 ± 8.11%), these differences were not statistically significant (Table 5).

Table 5 Demographic and clinical features of ACHD event-free survivors (censored) and those who died or survived SCD
Full size table

In terms of HRV measurements, when HRV measurements were compared between event-free survivors and those who died or survived SCD, decreases in HRV were observed in the patient group that comprised deceased and SCD survivors (lnASDNN: 3.73 ± 0.55 ms vs. 4.07 ± 0.36 ms, p = 0.04; lnPNN30: 2.25 ± 1.51% vs. 2.97 ± 0.75%, p = 0.04; lnVFL: 6.80 ± 0.89 ms2 vs. 7.50 ± 0.74 ms2, p = 0.03; lnLF: 5.28 ± 1.76 ms2 vs. 6.47 ± 0.83 ms2, p < 0.01; Fig. 1).

Fig. 1
figure 1

HRV measurements in event-free ACHD survivors (censored) and patients who died or survived cardiac arrest during follow-up. Abbreviations: ASDNN: average of the standard deviations of normal RR intervals for each 5-min segment; LF: low frequency; LN: natural logarithm; PNN30: percentage of RR intervals differing by more than 30 ms; VLF: very low frequency

Full size image

On univariate Cox regression analysis, the time domain indices lnSDNN, lnASDNN and lnPNN30, as well as the frequency domain parameters lnTP, lnVLF and lnLF were associated with death or survived SCD (Table 6). In due consideration of the low event rate (n = 11), no additional multivariate Cox proportional hazard regression analysis was performed [12].

Table 6 Univariate Cox regression analysis
Full size table

Discussion

The present study prospectively analysed HRV alterations and their association with outcome in ACHD patients. The main results are as follows:

  1. 1)

    When compared to healthy controls, ACHD patients exhibited an impairment in HRV as assessed by time and frequency domain analysis.

  2. 2)

    HRV measurements did not differ over ACHD lesion groups.

  3. 3)

    Both frequency and time domain indices carried prognostic implication on ACHD mortality and survived cardiac arrest.

Arrhythmias are a leading cause of hospitalization and cardiac death in the ACHD population [13, 14]. The aetiologies from which ACHD patients are subject to rhythm disorders comprise arrhythmic sequelae associated with the specific underlying heart defect, conduction abnormalities, surgical scar, hypoxia and abnormal pressure/volume loads of long duration [15]. As a consequence of the high incidence and prognostic implication of arrhythmias, early diagnosis is desirable. In general terms, the autonomic nervous system plays an important role in the initiation and sustaining of arrhythmias. It is the prime regulator of heart rate and determines HRV [6]. HRV, i.e., the amount of heart rate fluctuation around the mean heart rate, can be quantified by different methods of which time and frequency domain analysis represents a non-invasive approach of good reproducibility. The traditional applications of HRV measurement are the surveillance of post-myocardial infarction and diabetic patients. Moreover, decreased HRV has also been shown to be present and to serve as a strong and independent predictor of adverse outcome in patients with stable coronary heart disease, heart failure, atrial fibrillation and pulmonary hypertension [16, 17]. The value of HRV analysis in the field of ACHD has been subject of recent research. These studies have principally focused on single defects and the impact of previous surgical repair on HRV. In an ACHD cohort of 30 surgically closed and 30 unrepaired ventricular septal defects that underwent time domain analysis, Maagard et al. ascertained an impaired HRV and higher proportion of PVC in ACHD patients when compared to their healthy peers. Differences were highest amongst patients with surgically closed ventricular septal defects [18]. Caution should be made in direct comparison of Maagard´s results to our observations as HRV indices did not undergo logarithmic transformation. Moreover, we additionally measured frequency domain indices. Except for HF and total power, frequency domain measurements were significantly impaired in ACHD patients, irrespective of the underlying ACHD lesion group. In light of our findings, it is worth considering briefly the separate rhythmic contributions of sympathetic and parasympathetic autonomic activity. While sympathetic activity modulates heart rate in the low frequency range (0.04–0.15 Hz), parasympathetic activity is related to the high frequency range (0.15–0.40 Hz) [6, 19]. In keeping with this and the currently observed unaffected HF spectrum among ACHD patients, our results hint at an autonomic dysfunction that primarily affects the sympathetic branch, whilst the parasympathetic tone is mainly preserved.

With regard to the prognostic value of HRV measurements, several time and frequency domain indices were presently identified to be associated with mortality in ACHD on univariate regression analysis. Taking into account the recommended number of 10 events per independent variable in proportional hazards regression analyses [12] and the currently observed event rate of 8 deaths, no multivariate analysis was performed. Decreases in SDNN and VFL power have been reported to predict outcome in patients with acute myocardial infarction [20]. In stable angina pectoris, alterations in frequency domain measurements have been shown to independently predict cardiovascular death [21]. In the UK-HEART study, the HRV measurement SDNN was the most powerful predictor of mortality due to progressive heart failure [22]. However, HRV analysis was confined to time domain measurement, frequency domain indices were not assessed. Within the field of ACHD, Lammers et al. examined HRV by time domain analysis and additionally assessed heart rate turbulence in 43 ACHD patients [5]. They identified pathologic heart rate turbulence to be the only independent predictor of all-cause mortality, whilst time domain measures had no predictive value. These results are only partially comparable with our observations. Consistent with Lammers and colleagues, we ascertained the time domain index SDNN to be associated with mortality. Contrary to them, we additionally performed frequency domain analysis and hereby obtained a wide range of parameters that were related to death. However, the question whether theses indices independently carry prognostic implication could not be answered definitively in due consideration of the limited number of deaths observed.

There are several limitations that should be addressed. First, we assume that selection and procedure bias might have arisen from our single-centre study design. This single-site character impeded the enrolment of a larger number of controls and ACHD patients with higher event rates and the option to perform multivariate hazard regression analysis. Secondly, we subdivided ACHD patients according to their haemodynamics to assess intergroup differences. It adheres to current guidelines, but might entail the risk of disregarding other, more appropriate discriminants. Finally, our ACHD patient cohort encompassed a broad spectrum of congenital heart lesions within which some defects were underrepresented. It thereby restricts generalizability of our study results.

In conclusion, ACHD is accompanied by HRV impairment. Altered time and frequency domain indices carry prognostic information. Our results set the stage for larger trials with higher patient numbers and longer duration of follow-up to confirm the predictive value of HRV measurements and deduce preventive approaches.

Availability of data and materials

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Baumgartner H, De Backer J, Babu-Narayan SV, Budts W, Chessa M, Diller GP, Lung B, Kluin J, Lang IM, Meijboom F, Moons P, Mulder BJM, Oechslin E, Roos-Hesselink JW, Schwerzmann M, Sondergaard L, Zeppenfeld K; ESC Scientific Document Group. 2020 ESC Guidelines for the management of adult congenital heart disease. Eur Heart J. 2021;42:563–645.

    Article  Google Scholar 

  2. Khairy P, Van Hare GF, Balaji S, Berul CI, Cecchin F, Cohen MI, Daniels CJ, Deal BJ, Dearani JA, Groot Nd, Dubin AM, Harris L, Janousek J, Kanter RJ, Karpawich PP, Perry JC, Seslar SP, Shah MJ, Silka MJ, Triedman JK, Walsh EP, Warnes CA. PACES/HRS Expert Consensus Statement on the Recognition and Management of Arrhythmias in Adult Congenital Heart Disease: developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology (ACC), the American Heart Association (AHA), the European Heart Rhythm Association (EHRA), the Canadian Heart Rhythm Society (CHRS), and the International Society for Adult Congenital Heart Disease (ISACHD). Heart Rhythm. 2014;11:e102-165.

    Article  PubMed  Google Scholar 

  3. Davos CH, Davlouros PA, Wensel R, Francis D, Davies LC, Kilner PJ, Coats AJ, Piepoli M, Gatzoulis MA. Global impairment of cardiac autonomic nervous activity late after repair of tetralogy of Fallot. Circulation. 2002;106:I69-75.

    Article  PubMed  Google Scholar 

  4. Davos CH, Francis DP, Leenarts MF, Yap SC, Li W, Davlouros PA, Wensel R, Coats AJ, Piepoli M, Sreeram N, Gatzoulis MA. Global impairment of cardiac autonomic nervous activity late after the Fontan operation. Circulation. 2003; 108:II180–185.

  5. Lammers A, Kaemmerer H, Hollweck R, Schneider R, Barthel P, Braun S, Wacker A, Brodherr-Heberlein S, Hauser M, Eicken A, Schmidt G, Hess J. Impaired cardiac autonomic nervous activity predicts sudden cardiac death in patients with operated and unoperated congenital cardiac disease. J Thorac Cardiovasc Surg. 2006;132:647–55.

    Article  PubMed  Google Scholar 

  6. Rajendra Acharya U, Paul Joseph K, Kannathal N, Lim CM, Suri JS. Heart rate variability: a review. Med Biol Eng Comput. 2006;44:1031–51.

    Article  CAS  PubMed  Google Scholar 

  7. Buccelletti E, Gilardi E, Scaini E, Galiuto L, Persiani R, Biondi A, Basile F, Silveri NG. Heart rate variability and myocardial infarction: systematic literature review and metanalysis. Eur Rev Med Pharmacol Sci. 2009;13:299–307.

    CAS  PubMed  Google Scholar 

  8. Fauchier L, Babuty D, Cosnay P, Fauchier JP. Prognostic value of heart rate variability for sudden death and major arrhythmic events in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1999;33:1203–7.

    Article  CAS  PubMed  Google Scholar 

  9. Stout KK, Daniels CJ, Aboulhosn JA, Bozkurt B, Broberg CS, Colman JM, Crumb SR, Dearani JA, Fuller S, Gurvitz M, Khairy P, Landzberg MJ, Saidi A, Valente AM, Van Hare GF. 2018 AHA/ACC Guideline for the management of adults with congenital heart disease: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2019;73:1494–563.

    Article  PubMed  Google Scholar 

  10. Di Salvo G, Miller O, Babu Narayan S, Li W, Budts W, Valsangiacomo Buechel ER, Frigiola A, van den Bosch AE, Bonello B, Mertens L, Hussain T, Parish V, Habib G, Edvardsen T, Geva T, Baumgartner H, Gatzoulis MA; 2016–2018 EACVI Scientific Documents Committee. Imaging the adult with congenital heart disease: a multimodality imaging approach-position paper from the EACVI. Eur Heart J Cardiovasc Imaging. 2018; 19:1077-1098

  11. Bozkurt B, Coats AJS, Tsutsui H, Abdelhamid CM, Adamopoulos S, Albert N, Anker SD, Atherton J, Böhm M, Butler J, Drazner MH, Michael Felker G, Filippatos G, Fiuzat M, Fonarow GC, Gomez-Mesa JE, Heidenreich P, Imamura T, Jankowska EA, Januzzi J, Khazanie P, Kinugawa K, Lam CSP, Matsue Y, Metra M, Ohtani T, Francesco Piepoli M, Ponikowski P, Rosano GMC, Sakata Y, Seferović P, Starling RC, Teerlink JR, Vardeny O, Yamamoto K, Yancy C, Zhang J, Zieroth S. Universal definition and classification of heart failure. Eur J Heart Fail. 2021;23:352–80.

    Article  PubMed  Google Scholar 

  12. Peduzzi P, Concato J, Feinstein AR, Holford TR. Importance of events per independent variable in proportional hazards regression analysis. II. Accuracy and precision of regression estimates. J Clin Epidemiol. 1995;48:1503–10.

    Article  CAS  PubMed  Google Scholar 

  13. Opotowsky AR, Siddiqi OK, Webb GD. Trends in hospitalizations for adults with congenital heart disease in the U.S. Am Coll Cardiol. 2009;54:460–7.

    Article  Google Scholar 

  14. Diller GP, Kempny A, Alonso-Gonzalez R, Swan L, Uebing A, Li W, Babu-Narayan S, Wort SJ, Dimopoulos K, Gatzoulis MA. Survival prospects and circumstances of death in contemporary adult congenital heart disease patients under follow-up at a large tertiary centre. Circulation. 2015;132:2118–25.

    Article  PubMed  Google Scholar 

  15. Khairy P. Ventricular arrhythmias and sudden cardiac death in adults with congenital heart disease. Heart. 2016;102:1703–9.

    Article  Google Scholar 

  16. Routledge HC, Chowdhary S, Townend JN. Heart rate variability—a therapeutic target? J Clin Pharm Ther. 2002;27:85–92.

    Article  CAS  PubMed  Google Scholar 

  17. Witte C, Meyer-Arend MZHG, JU, Andrié R, Schrickel JW, Hammerstingl C, Schwab JO, Nickenig G, Skowasch D, Pizarro C. Heart rate variability and arrhythmic burden in pulmonary hypertension. Adv Exp Med Biol. 2016;934:9–22.

  18. Maagaard M, Eckerström F, Hjortdal VE. Cardiac arrhythmias and impaired heart rate variability in older patients with ventricular septal defects. J Am Heart Assoc. 2021;10.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shaffer F, Ginsberg JP. An Overview of Heart Rate Variability Metrics and Norms. Front Public Health. 2017;5:258.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Xu Y, Yu Y, He L, Wang Y, Gu Y. Predicting efficacy of combined assessment with fragmented QRS and severely depressed heart rate variability on outcome of patients with acute myocardial infarction. Heart Vessels. 2022;37:239–49.

    Article  PubMed  Google Scholar 

  21. Forslund L, Björkander I, Ericson M, Held C, Kahan T, Rehnqvist N, Hjemdahl P. Prognostic implications of autonomic function assessed by analyses of catecholamines and heart rate variability in stable angina pectoris. Heart. 2002;87:415–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nolan J, Batin PD, Andrews R, Lindsay SJ, Brooksby P, Mullen M, Baig W, Flapan AD, Cowley A, Prescott RJ, Neilson JM, Fox KA. Prospective study of heart rate variability and mortality in chronic heart failure: results of the United Kingdom heart failure evaluation and assessment of risk trial (UK-heart). Circulation. 1998;98:1510–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Open Access funding enabled and organized by Projekt DEAL. No funding was received for this research.

Author information

Author notes

  1. Carmen Pizarro and Franziska Luise Bosse contributed equally to this work.

Authors and Affiliations

  1. University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany

    Carmen Pizarro, Franziska Luise Bosse, Charlotte Begrich, Barbora Reznakova, Thomas Beiert, Jan Wilko Schrickel, Georg Nickenig, Dirk Skowasch & Diana Momcilovic

Authors
  1. Carmen Pizarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Franziska Luise Bosse
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charlotte Begrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barbora Reznakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas Beiert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan Wilko Schrickel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Georg Nickenig
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dirk Skowasch
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Diana Momcilovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: Carmen Pizarro, Thomas Beiert, Jan Wilko Schrickel, Georg Nickenig, Dirk Skowasch and Diana Momcilovic. Data acquisition: Barbora Reznakova, Charlotte Begrich and Franziska Luise Bosse. Writing – original draft preparation: Carmen Pizarro. Writing – review and editing: Thomas Beiert, Jan Wilko Schrickel, Georg Nickenig, Dirk Skowasch and Diana Momcilovic. Writing – final version: Carmen Pizarro. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Carmen Pizarro.

Ethics declarations

Ethics approval and consent to participate

Approval was obtained from the local ethic committee of the faculty of medicine of the University of Bonn (Germany). The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable.

Competing interests

The authors have no competing interests to declare that are relevant to the content of this article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pizarro, C., Bosse, F.L., Begrich, C. et al. Cardiac autonomic dysfunction in adult congenital heart disease. BMC Cardiovasc Disord 23, 513 (2023). https://0-doi-org.brum.beds.ac.uk/10.1186/s12872-023-03558-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/s12872-023-03558-4

Keywords

BMC Cardiovascular Disorders

ISSN: 1471-2261

Contact us