|Year : 2019 | Volume
| Issue : 1 | Page : 8-12
Heart rate variability study in adult Nigerian subjects with sickle cell disease during vaso-occlusive crisis
Adewole Adesoji Adebiyi1, Olaniyi Mabayomije Oyebowale2, Ayodele John Olaniyi3, Ayodele Olawale Falase4
1 Department of Medicine, College of Medicine, University of Ibadan; Department of Medicine, University College Hospital, Ibadan, Nigeria
2 Department of Medicine, University College Hospital, Ibadan; Department of Medicine, State Hospital, Abeokuta, Nigeria
3 Department of Haematology, College of Medicine, University of Ibadan; Department of Haematology, University College Hospital, Ibadan, Nigeria
4 Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
|Date of Web Publication||12-Mar-2019|
Adewole Adesoji Adebiyi
Department of Medicine, College of Medicine, University of Ibadan, Ibadan
Source of Support: None, Conflict of Interest: None
Context: Autonomic nervous system (ANS) dysfunction assessed by abnormalities in heart rate variability (HRV) is thought to play a role in the pathophysiology of sickle cell disease (SCD). There is suggestion that changes in ANS may occur in SCD subjects during episodes of vaso-occlusive crises (VOC). Aims: The aim of this study was to evaluate the ANS by determining the HRV in patients with SCD during VOC. Settings and Design: This was a cross-sectional observational study. Materials and Methods: HRV studies were carried out in 76 participants with SCD during episodes of VOC. Eighty-two SCD participants in steady state served as controls. Statistical Analysis Used: Comparison of two independent groups with Student's t-test and Mann–Whitney's test, and multiple linear regressions were also carried out. Results: Participants with SCD and VOC had significant reductions in the time-domain HRV parameters of standard deviation of RR intervals (45.8 [59.36] ms vs. 66.3 [129.2] ms, P = 0.0073) and root mean square of successive differences of RR intervals (48.3 [87.66] ms vs. 74.2 [174.5] ms, P = 0.0015). The frequency-domain HRV indices of low frequency (145.8 [81.62] ms2 vs. 157.5 [68.9] ms2, P = 0.1442) and high frequency (145.0 [118.40] ms2 vs. 146.3 [90.3] ms2, P = 0.3683) were similar between the two groups. Age and the heart rate were the major independent relations of the HRV parameters. Conclusions: Time-domain HRV parameters were impaired during crises in participants with SCD. This finding suggests further impairment of ANS activity in SCD patients during crises. Further studies are needed to clarify the prognostic implication of these findings.
Keywords: Autonomic nervous system, heart rate variability, sickle cell disease, vaso-occlusive crisis
|How to cite this article:|
Adebiyi AA, Oyebowale OM, Olaniyi AJ, Falase AO. Heart rate variability study in adult Nigerian subjects with sickle cell disease during vaso-occlusive crisis. Niger Postgrad Med J 2019;26:8-12
|How to cite this URL:|
Adebiyi AA, Oyebowale OM, Olaniyi AJ, Falase AO. Heart rate variability study in adult Nigerian subjects with sickle cell disease during vaso-occlusive crisis. Niger Postgrad Med J [serial online] 2019 [cited 2020 Feb 22];26:8-12. Available from: http://www.npmj.org/text.asp?2019/26/1/8/253981
| Introduction|| |
Sickle cell disease (SCD) is an inherited blood disorder primarily affecting groups within endemic malaria areas, especially of African descent. Sickle cell crises are periods of acute deterioration in level of functioning in SCD patients usually precipitated by infection, dehydration, cold and hypoxia. Cardiovascular system abnormalities are common causes of morbidity and mortality in SCD patients. Cardiovascular causes are increasingly being recognised as major contributor to premature mortality in patients with SCD. It has also been noted that a large number of deaths in SCD occur during episodes of vaso-occlusive crises (VOC), and these deaths were largely unexplained.
Abnormalities in the autonomic nervous system (ANS) function have been identified in recent years, a major contributor to morbidity and mortality in several disease states., Heart rate variability (HRV) had emerged as a non-invasive electrocardiographic marker of the influence of the activities of the sympathetic and parasympathetic components of the ANS on the sinoatrial node of the heart. A normal heart with a well-functioning ANS elicits beat-to-beat variation in the heart rate reflecting a balanced sympathovagal state, while an abnormal heart exhibits an altered sympathovagal balance and hence diminished HRV resulting from changes in the activities of the afferent and efferent fibres of the ANS and in the local neural regulation of the heart.
Several studies had reported abnormalities in the ANS function in patients with SCD.,,, It has also been suggested that the abnormalities of the ANS function are more marked in SCD patients with more severe disease., ANS dysfunction is therefore thought to play a role in the pathophysiology of SCD., A recent study suggested that ANS activity might be reduced in participants with SCA during VOC. The aim of the study is to evaluate the ANS, using HRV, in participants with SCD during episodes of VOC.
| Materials and Methods|| |
The study, a cross-sectional comparative one, was carried out at the Haematology Day care Unit, Medical Outpatient Clinics and Medical Wards of the University College Hospital, Ibadan, after due ethical clearance has been obtained from the Joint Institution Review Committee of the University of Ibadan and University College Hospital, Ibadan (IRB No UI/EC/12/0121). Data collection was performed between July 2012 and January 2013. The study was carried out in accordance with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all participants included in the study.
Subjects and controls
The study participants were adult Nigerians with haemoglobin genotype S presenting during VOC at the Haematology Day care Clinic and Medical Outpatient Clinics of the hospital. Vaso-occlusive crisis was defined as the occurrence of pain in the extremities, back, abdomen, chest or head that lasted for at least 2 h necessitating hospital visit and could not be explained by any other means except SCD and was similar to patient's usual form of presentation during crises. Controls were recruited from patients with haemoglobin genotype S who were in the steady state.
Participants were excluded if they had a history of cardiac disease, renal disease, bronchial asthma, systemic hypertension and diabetes. They were also excluded if they were receiving cardioactive medications such as beta-blockers, cardiac glycosides and antiarrhythmic drugs or other drugs known to affect autonomic functions such as antidepressants, diuretics, antihistamines, cough and cold preparations and aspirin. Participants were also excluded if they had features that were not suggestive of VOC such as worsening jaundice, marked pallor, haemoglobinuria and/or features of sequestration crisis (sudden pallor, weakness, with a rapidly enlarging abdomen). Participants and controls with features of congenital and/or acquired heart diseases, evidence of pregnancy and intercurrent illnesses were also excluded from the study.
Sample size and power calculation
The study was powered at 90% to detect a minimum difference of 10 normalised unit in the high-frequency (HF) power between the participants in crises and controls. The sample size formula used is:
where u is one-sided percentage point of the normal distribution corresponding to 100% – power, that is, with power at 90%, u is 1.28, v is percentage point of the normal distribution corresponding to the (two-sided) significance level that is, v = 1.96, σ1 and σ2 are the standard deviation of the means of the values in the two groups and M is the difference to be observed between the means. Using the σ1 and σ2 from the study of Charlot et al., the minimum number of 72 participants per group was required for the study.
Clinical data and sample collection
After providing written informed consent, all participants underwent clinical examination. Sociodemographic details including age, gender, lifestyle, personal and family histories of SCDs, hospitalisation and presence of symptoms of sickle cell crisis were obtained. Participants were considered as having frequent crises if they had crises three times or more in the preceding year. Participants were also considered as having frequent blood transfusions if they have had three or more episodes of blood transfusions. The participants' weight and height were taken using a standard weighing scale and stadiometer, respectively. Measurements were taken with the shoes removed and in light clothing. Weights were measured to the nearest 0.5 kg and height to the nearest 0.5 cm. Blood pressure was measured according to the standard guidelines.
Heart rate variability
HRV studies were carried out with the participant lying comfortably as possible in supine position. For ethical reasons, HRV studies were carried out after the participants with VOC had been stabilised and initial analgesic administered. The controls had been instructed to avoid coffee, tea, alcohol and food for at least 2 h before the HRV recordings. The HRV measurements were carried out in a quiet, slightly illuminated room. The participants were instructed to relax and breathe normally during the recordings.
The duration of the electrocardiography (ECG) recording for the HRV study was 5 min. The HRV recordings were obtained from leads V5 and V6 of the electrocardiogram. The HRV parameters acquired were according to the North American Society for Pacing and Electrophysiology/European Society of Cardiologists guidelines using a commercial PC-ECG 1200 h recorder (software version 5.0) (Norav Medical Inc., Israel). Measurements were acquired at a sampling rate of 1000 Hz. Very low-frequency (LF), LF and HF bands were analysed between 0.0033–0.04 Hz, 0.04–0.15 Hz and 0.15–0.4 Hz, respectively.
The measured HRV parameters include: time-domain parameters such as minimal RR, Maximal RR, average RR, average heart rate and standard deviation of RR intervals (SDNN) representing the cyclic variability of the heart rate during the recording period; root mean square of successive differences of RR intervals (rMSSD) and pNN50, which denote the per cent of RR intervals differing by >50 ms from the preceding one. Power spectral analysis was conducted using the non-parametric fast Fourier transformation method. Frequency-domain parameters generated include LF, HF and LF/HF ratio.
Data management and statistical analysis
Data were analysed by R statistical software version 3.3.2. The parameters were expressed as means (standard deviation) for continuous variables while categorical variables were presented as frequency and proportions. The Shapiro–Wilk's test was used to assess the normality of the data distribution. As the HRV data were highly skewed and not normally distributed, the differences in the HRV parameters between the participants and controls were compared with the Mann–Whitney's test. Categorical variables were compared with the Chi-squared analysis. Multiple linear regression analyses were carried out to determine the independent relations of the various HRV parameters. The level of statistical significance was fixed at P < 0.05.
| Results|| |
Seventy-six participants with sickle cell anaemia who were in VOC and 82 participants with SCD who were in steady state were evaluated. The ages of the participant ranged from 16 to 60 years. [Table 1] shows the baseline characteristics of the participants. The groups were comparable with respect to age, gender distribution, body weight, height, body mass index and their steady state haematocrit. There were no differences in the frequencies of crises and blood transfusion between the two groups. However, the participants in crises had elevated heart rates, blood pressures and body temperature when compared with the participants in a steady state.
[Table 2] shows the HRV parameters of the participants. The maximal RR, minimal RR and the average RR intervals were shorter in the participants with crises. The time-domain HRV parameters of SDNN and rMSSD were shorter in the participants in VOC when compared with the participants in the steady state [Figure 1]. There were no significant differences in the frequency-domain parameters of HRV between the participants and the controls. [Table 3] shows the regression coefficients obtained from the various multiple linear models of HRV parameters as the dependent variables. The heart rate and age were the major independent relations of most of the HRV models examined.
|Figure 1: Standard deviation of RR intervals in the participants and controls. The horizontal line is the median of each group|
Click here to view
|Table 3: Multiple linear regression coefficients for heart rate variability parameters in the participants|
Click here to view
| Discussion|| |
This study demonstrates mainly a reduction in the time-domain HRV indices of SDNN, rMSSD and an increase in the frequency-domain HRV index of total power among participants with SCD during VOC. The increased heart rate in the participants during crises and age were the main independent correlates of the altered HRV indices seen among our study participants.
HRV has been established as a marker of ANS activity and abnormalities of HRV have been observed to be of prognostic importance in several disease states., Several studies on participants with SCD had suggested abnormal autonomic system activity. Inamo et al. using HRV found impaired ANS activity in sickle cell patients when compared to normal controls. Romero Mestre et al. demonstrated abnormal values for cardiovascular autonomic function tests when compared with controls and suggested that the involvement of ANS might be related to the occurrence of sudden deaths in participants with SCD. Nebor et al. noted that SCD participants with frequent crises had impaired parasympathetic activity and marked sympathovagal imbalance when compared with the SCD with infrequent crises.
Our participants with SCD had significant reductions in the SDNN, rMSSD suggesting a reduction in HRV during episodes of sickling crises. HRV parameters of rMSSD, NN50 and pNN50 are thought to be primarily affected by vagal influence during respiration while SDNN, NN50 and pNN50 reflect active ANS and good compliance of the heart to autonomic innervation. This impaired HRV during crises might be a factor in the pathophysiology of unexplained sudden deaths that have been documented in participants with SCD during episodes of crises.
However, the frequency-domain HRV parameters of HF, LF and the LF/HF ratio were similar between the two groups. The HF component is thought to be dependent on vagal activity while the LF reflects both sympathetic and parasympathetic balance and might also be influenced by baroreceptors. Charlot et al. in a study of participants with SCD during and after VOC observed a reduction of the frequency-domain parameters of HF and LF/HF indicating parasympathetic withdrawal in the participants during VOC. Our study, however, did not observe any difference in HF and LF/HF ratio possibly due to the fact that our participants had received some analgesic treatment which could have influenced our results.
Our study supported previous findings of the interrelationship of HRV parameters and the heart rate in that the heart rate was a major determinant of HRV parameters in the participants. There have been suggestions for normalising the HRV parameters for the changes in heart rate, and Pradhapan et al. analysing the data from the finish cardiovascular study observed that predictive capacity of HRV during rest and recovery could be augmented when its dependence on heart rate is diminished by applying correction procedures. However, applying a correction factor for heart rate did not significantly alter the differences observed in the HRV parameters between SCD participants in crises and steady state. Increased heart rate and reduced HRV have been associated with subclinical elevation of inflammatory markers in healthy participants and in those with coronary artery disease., This association is thought to be attributable to deficits in the parasympathetic modulation of immunity and coagulation. Etienne-Julan et al. had observed elevated inflammatory markers in children with SCD during episodes of VOC crises. It could be suggested that the altered immunity and inflammatory responses that are aggravated during VOC crises could play significant roles in the pathogenesis of sudden death that occurs in participants with SCD during crises. Further studies evaluating the relationship between ANS dysfunction, crises and inflammatory state are needed.
Furthermore, in consonance with the previous findings, we found an inverse, independent relationship between HRV and age. Several studies have documented this relationship between age and HRV., It is thought that the age-related reduction in HRV is consequent to the decline in the autonomic function with advancing age. This decline in ANS function with age may contribute to the onset of cardiovascular disease by lowering the threshold for the manifestation of heart disease and also provide a substrate for arrhythmias which thus complicate the course of SCD.
Previous studies had highlighted the relationship of ANS dysfunction and the severity of the SCD phenotype, and had suggested that ANS impairment plays a role in the pathophysiology of SCD. In our study, however, there were no independent relationships between the HRV and severity of the SCD state evident by frequent crises and frequent blood transfusions. Further studies are needed to examine the role of ANS dysfunction in the severity of SCD.
Our study is limited by our inability to repeat the HRV measurements after the crises episodes in order to determine whether the changes observed were reversible given the fact that the significantly increased heart rate during the crises period was the major determinant of the changes in the HRV parameters. Furthermore, the absence of normative values for short-term HRV parameters for participants in our environment makes it difficult to establish cut-off points for the abnormal HRV in the participants.
| Conclusions|| |
We observed that SCD participants had reduced HRV during VOC, especially the time-domain HRV parameters when compared with SCD participants in the steady state. Furthers studies are needed to evaluate the prognostic importance of this finding in participants with SCD.
Financial support and sponsorship
This study was financially supported by Equipment from MacArthur Foundation Multidisciplinary Research Support Grant 800/406/54/01/D/2008/3.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Gladwin MT, Sachdev V. Cardiovascular abnormalities in sickle cell disease. J Am Coll Cardiol 2012;59:1123-33.
Fitzhugh CD, Lauder N, Jonassaint JC, Telen MJ, Zhao X, Wright EC, et al.
Cardiopulmonary complications leading to premature deaths in adult patients with sickle cell disease. Am J Hematol 2010;85:36-40.
Parfrey NA, Moore W, Hutchins GM. Is pain crisis a cause of death in sickle cell disease? Am J Clin Pathol 1985;84:209-12.
Stauss HM. Heart rate variability. Am J Physiol Regul Integr Comp Physiol 2003;285:R927-31.
Kleiger RE, Stein PK, Bigger JT Jr. Heart rate variability: Measurement and clinical utility. Ann Noninvasive Electrocardiol 2005;10:88-101.
Sztajzel J. Heart rate variability: A noninvasive electrocardiographic method to measure the autonomic nervous system. Swiss Med Wkly 2004;134:514-22.
van Ravenswaaij-Arts CM, Kollée LA, Hopman JC, Stoelinga GB, van Geijn HP. Heart rate variability. Ann Intern Med 1993;118:436-47.
Inamo J, Connes P, Barthélémy JC, Dan V, Coates T, Loko G, et al.
Pulmonary hypertension does not affect the autonomic nervous system dysfunction of sickle cell disease. Am J Hematol 2009;84:311-2.
Romero Mestre JC, Hernández A, Agramonte O, Hernández P. Cardiovascular autonomic dysfunction in sickle cell anemia: A possible risk factor for sudden death? Clin Auton Res 1997;7:121-5.
Pearson SR, Alkon A, Treadwell M, Wolff B, Quirolo K, Boyce WT, et al.
Autonomic reactivity and clinical severity in children with sickle cell disease. Clin Auton Res 2005;15:400-7.
Oguanobi NI, Onwubere BJ, Anisiuba BC, Ike SO, Ejim EC, Ibegbulam OG, et al.
Clinical findings associated with cardiovascular autonomic dysfunction in adult sickle cell anaemia patients. Acta Cardiol 2012;67:169-75.
Nebor D, Bowers A, Hardy-Dessources MD, Knight-Madden J, Romana M, Reid H, et al.
Frequency of pain crises in sickle cell anemia and its relationship with the sympatho-vagal balance, blood viscosity and inflammation. Haematologica 2011;96:1589-94.
Connes P. Altered autonomic nervous system function in sickle cell disease. Am J Respir Crit Care Med 2011;184:398-400.
Connes P, Coates TD. Autonomic nervous system dysfunction: Implication in sickle cell disease. C R Biol 2013;336:142-7.
Charlot K, Hierso R, Lemonne N, Romana M, Tressières B, Lalanne-Mistrih ML, et al.
Changes in autonomic nervous activity during vaso-occlusive crisis in patients with sickle cell anaemia. Br J Haematol 2017;177:484-6.
Ballas SK. More definitions in sickle cell disease: Steady state v base line data. Am J Hematol 2012;87:338.
Kirkwood BR, Stern AC. Essential Medical Statistics. 2nd
ed. Oxford, UK. Blackwell Science Ltd.; 2003.
Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, et al.
Recommendations for blood pressure measurement in humans and experimental animals: Part 1: Blood pressure measurement in humans: A statement for professionals from the subcommittee of professional and public education of the American Heart Association council on high blood pressure research. Hypertension 2005;45:142-61.
Heart rate variability: Standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American society of pacing and electrophysiology. Circulation 1996;93:1043-65.
R Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: Foundation for Statistical Computing; 2016. Available from: https://www.R-project.org/
. [Last accessed on 2016 Oct 15].
Sacha J. Interaction between heart rate and heart rate variability. Ann Noninvasive Electrocardiol 2014;19:207-16.
Sacha J, Pluta W. Different methods of heart rate variability analysis reveal different correlations of heart rate variability spectrum with average heart rate. J Electrocardiol 2005;38:47-53.
Sacha J. Why should one normalize heart rate variability with respect to average heart rate. Front Physiol 2013;4:306.
Pradhapan P, Tarvainen MP, Nieminen T, Lehtinen R, Nikus K, Lehtimäki T, et al.
Effect of heart rate correction on pre- and post-exercise heart rate variability to predict risk of mortality-an experimental study on the FINCAVAS cohort. Front Physiol 2014;5:208.
Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Abedini S, Hansen JF, et al.
Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J 2004;25:363-70.
Haensel A, Mills PJ, Nelesen RA, Ziegler MG, Dimsdale JE. The relationship between heart rate variability and inflammatory markers in cardiovascular diseases. Psychoneuroendocrinology 2008;33:1305-12.
Pavlov VA, Tracey KJ. The cholinergic anti-inflammatory pathway. Brain Behav Immun 2005;19:493-9.
Etienne-Julan M, Belloy MS, Decastel M, Dougaparsad S, Ravion S, Hardy-Dessources MD, et al.
Childhood sickle cell crises: Clinical severity, inflammatory markers and the role of interleukin-8. Haematologica 2004;89:863-4.
Agelink MW, Malessa R, Baumann B, Majewski T, Akila F, Zeit T, et al.
Standardized tests of heart rate variability: Normal ranges obtained from 309 healthy humans, and effects of age, gender, and heart rate. Clin Auton Res 2001;11:99-108.
Zhang J. Effect of age and sex on heart rate variability in healthy subjects. J Manipulative Physiol Ther 2007;30:374-9.
Beckers F, Verheyden B, Aubert AE. Aging and nonlinear heart rate control in a healthy population. Am J Physiol Heart Circ Physiol 2006;290:H2560-70.
Strait JB, Lakatta EG. Aging-associated cardiovascular changes and their relationship to heart failure. Heart Fail Clin 2012;8:143-64.
Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res 2014;114:1004-21.
[Table 1], [Table 2], [Table 3]