Sympathovagal imbalance decades after atrial septal defect repair: a long-term follow-up study

Sympathovagal imbalance decades after atrial septal defect repair: a long-term follow-up study.

Alstrup M, Karunanithi Z, Maagaard MØ, Poulsen SH, Hjortdal VE.Eur J Cardiothoracic Surg. 2021 May 20:ezab235. doi: 10.1093/ejcts/ezab235. Online ahead of print.PMID: 34015096


Take Home Points:

  • Patients with corrected atrial septal defect (ASD) have increased morbidity and mortality as compared to the general population
  • Autonomic cardiac function, assessed non-invasively by heart rate variability (HRV) markers during 48h Holter monitoring, is abnormal in both surgically and percutaneously closed ASD patients as compared to age- and sex- matched healthy controls
  • The significance of abnormal HRV in corrected ASD patients remains unclear at this stage, but is a novel finding that warrants further consideration.

Dr Timothy Roberts

Commentary by Dr. Timothy Roberts (Melbourne, Australia), section editor of ACHD Journal Watch: Once regarded as a benign lesion following correction, it is now well appreciated that patients with a history of corrected atrial septal defect (ASD) carry an elevated risk of morbidities including conduction disease, atrial fibrillation, stroke and pneumonia, as well as increased mortality. Abnormalities in autonomic nervous system activity have been observed in cardiac disease and identified to offer prognostic information, with reduced heart rate variability (HRV) found to strongly correlate with all-cause mortality. In ASD patients, the long-term development of abnormal HRV and its significance has not been assessed. The current study aimed to study measures of HRV and autonomic function by 48 h Holter monitoring in adults with corrected ASD at least ten years after intervention.


This long-term observational follow-up study from Aarhus University Hospital, Denmark, consisted of three study groups: (i) 17 surgically closed ASDs, (ii) 18 percutaneously closed ASDs and (iii) 18 age- and sex-matched control subjects. Inclusion criteria were age of 2 or more years at the time of diagnosis and more than 3 years since the time of ASD closure. All patients had an isolated secundum ASD. Exclusion criteria were the presence of additional congenital cardiac defects, lung disease, ischaemic heart disease, diabetes, hypertension, valve pathology or associated syndromes. Patient demographics are illustrated in Table 1, with the only significant difference being the size of ASD between closure groups:



A 48h Holter monitor was analysed for six HRV time-domain parameters representing parasympathetic tone (4, 5) and combined parasympathetic and sympathetic function (1, 2, 3, 6):

  1. Standard deviation (SD) of all time intervals between normal R peaks (NN) (SDNN)
  2. SD of the average of the NN interval for all 5-min periods (SDANN)
  3. Mean of the SD of all normal NN interval for all 5-min periods (SDNNi)
  4. Root mean square of the sum of all differences between successive NN intervals (RMSSD)
  5. Percentage of successive NN intervals that differ by > 50 ms (pNN50)
  6. Integral of the density distribution divided by the maximum of the density distribution (meaning the total number of NN intervals divided by the number of NN intervals in the modal bin; “triangular index”).


SDNN was the primary endpoint, with the other 5 parameters forming secondary endpoints.

Time-domain variables are shown in Table 2, below:



Abnormalities in both parasympathetic and combined parasympathetic and sympathetic function domains were observed in both ASD groups. The surgically closed ASD cohort had decreased HRV in all six domains as compared to controls, while the device closure group had reduced HRV in 3 of 6 domains. Additionally, both surgically and percutaneously closed ASD groups had a lower maximum heart rate as compared to the controls (surgical ASD 141 +/- 22, percutaneous ASD 146 +/- 21, controls 162 +/- 19 bpm, P = 0.0051 and P = 0.0253, respectively).


A number of possibilities are suggested to explain these observations. The earlier volume-overload effect on atrial function may contribute to decreased HRV at a later stage. Surgical closure may directly or indirectly affect autonomic nerve supply to the heart. Ultimately, we are left to ask what do these findings signify, and can these HRV domains be linked to the increased risk for all-cause mortality following ASD closure? We don’t know the answer yet, but it is an intriguing proposition and perhaps time will