Diastolic function evaluation in children with ventricular arrhythmia.

doi:10.21203/rs.3.rs-2464700/v1

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Diastolic function evaluation in children with ventricular arrhythmia.

https://doi.org/10.21203/rs.3.rs-2464700/v1

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published 11 Apr, 2023

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Premature ventricular contractions(PVCs) are frequently seen in children. The diastolic function has not been investigated in PVC children. We evaluated the left ventricular diastolic function in PVC children with normal left ventricular systolic function to detect whether potential diastolic function disturbances influence physical performance.

In the study group (36 PVCs children) and the controls (33 healthy volunteers). Echocardiographical diastolic function parameters such as left atrial volume index(LAVI), left atrial strains (AC-R, AC-CT, AC-CD), E wave, E’ medial atrial tissue doppler velocity, E/E’ and isovolumic relaxation time (IVRT) were measured. In the CPET, oxygen uptake (VO2max) was registered.

Evaluation of diastolic function parameters revealed statically significant differences between the study and control group regarding Edt 176.58 ± 54.8ms vs 136.94 ± 27.8ms,p < 0.01; E/E’12.6 ± 3.0 vs. 6.7 ± 1.0,p < 0.01; IVRT 96.6 ± 19.09ms. vs. 72.86 ± 13.67 ms,p < 0.01, respectively. Left atrial function was impaired in the study group compared to controls: LAVI 25.3 ± 8.2ml/m² vs. 19.2 ± 7.5ml/m²,p < 0.01, AC-CT 34.8 ± 8.6% vs. 44.8 ± 11.8%,p < 0.01; AC-R-6.0 ± 4.9% vs. -11.5 ± 3.5%, p < 0.01, respectively. Statistically significant moderate, negative correlation between VO2max and E/E’(r =-0.33, p = 0.02) was found.

Left ventricular diastolic function is impaired and deteriorates with the arrhythmia burden increase in PVC children. Ventricular arrhythmia in young individuals may be related to the filling pressure elevation and drive to exercise capacity deterioration.

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Premature ventricular contractions (PVCs) are one of the most common rhythm disorders. They are frequently observed in children and adolescents without structural heart disease and are considered benign. However, this hypothesis is uncertain due to existing observations indicating some connections between PVCs and left ventricular systolic dysfunction [¹. Risk factors, such as frequent PVCs, short coupling intervals between the sinus and premature beat, retrograde P-waves, broad QRS complexes, and complex arrhythmia, may induce systolic dysfunction[^2–6.

Moreover, there are data in the literature showing that in adults with PVC and normal ejection fraction, some diastolic function parameters, such as left atrial volume or diastolic filling pressure of the left ventricle, are impaired^7,8. This issue has not been investigated in children. In the recent data from our center, it was detected that exercise capacity is lowered in young individuals with PVC and normal left ventricular systolic function[⁹. This finding raises the question, what is the reason for these circumstances? One of the hypotheses is that the reason for low exercise capacity is dyssynchronous contraction. Nevertheless, we know that left ventricular diastolic dysfunction relates to the decrease of exertion tolerance in some clinical scenarios^10–13.

Considering these data, we aimed to evaluate the left ventricular diastolic function in young individuals with frequent ventricular arrhythmia and normal left ventricular systolic function to detect whether potential diastolic function disturbances influence physical performance.

This presented study was conducted prospectively between January 2022 and June 2022. The study group consisted of 36 patients, in whom arrhythmia was detected by auscultation or ECG evaluation during preventive visits. The age- and sex-matched 33 healthy volunteers were enrolled during the same study period as a control group. Table 1. Detailed history regarding exercise activity was taken in all patients and children from the control group. They later underwent resting ECG, 24-hour Holter monitoring, and echocardiography. Additionally, the study group was asked about the detailed history of clinical signs and pharmacological treatment and was referred to CPET.

Table 1

Comparison of anthropometrical parameters in the study and control groups
Characteristic	Study group (n = 36)	Control group (n = 33)	MD/OR(95% CI)	p
Age, years	13.8 ± 2	13.2 ± 3	0.6(-0.6;1.8)	0.32
Height (cm)	164 ± 12	163.0 ± 14	1.0(-5.2;7.2)	0.92
Weight(kg)	53 ± 15	52 ± 16	3.6(-6.4;8.4)	0.88
BSA(m2)	1.58 ± 0.30	1.56 ± 0.25	0.0(-0.12;0.14)	0.86
BSA – body surface area, odds ratios(OR), mean/median differences(MD)

Table 2

Echocardiographic parameters of the systolic function in the study and control group
Echocardiographic parameter	Study group	Control group	MD / OR (95% CI)	p
LVDd (mm)	48.5 ± 4.8	47.4 ± 4.6	0.6 (-1.5;2.7)	0.59
LVDd (z-score)	0.5 ± 1.1	0.0 ± 1.1	0.3 (-0.03;1.3)	0.12
LVSd (mm)	29.3 ± 3.4	28.2 ± 3.2	0.8 (-0.4;2.6)	0.21
LVEF (%)	60.0 ± 6.6	62.2 ± 6.4	-2.2 (-5.3;-0.9)	0.13
LVDd – left ventricular end-diastolic dimension, LVSd - left ventricular end-systolic dimension LVEF – left ventricular ejection faction, odds ratios(OR), mean/median differences(MD)

Table 3

Comparison of the diastolic parameters in the study and control groups.
Characteristic	Study group	Control group	MD (95% CI)	p
E (cm/s)	89.28 ± 11.65	91.12 ± 14.72	2.16 (-3.87;8.19)	0.48
Edt (ms)	176.58 ± 54.80	136.94 ± 27.83	39.64 (21.44;57.84)	< 0.01
A (cm/s)	54.59 ± 13.24	53.04 ± 9.13	1.55 (-3.31;6.41)	0.53
E/A	1.66 (1.54;1.98)	1.69 (1.37;1.96)	-0.03 (-0.15;0.21)	0.84
IVRT (ms)	96.60 ± 19.09	72.86 ± 13.67	23.74 (16.68;30.81)	< 0.01
E' (cm/s)	12.57 ± 2.96	13.37 ± 1.86	-0.80 (-1.84;0.24)	0.13
A' (cm/s)	6.42 ± 1.68	6.61 ± 1.22	-0.18 (-0.81;0.44)	0.56
E'/A'	2.11 ± 0.80	2.09 ± 0.48	0.02 (-0.26;0.29)	0.89
E/E'	7.60 ± 1.81	6.73 ± 1.05	0.87 (0.25;1.49)	< 0.01
LAVI (ml/m2)	25.3 ± 8.2	19.2 ± 7.5	6.1 (2.6;9.6)	< 0.01
AC-R (%)	34.8 ± 8.6	44.8 ± 11.8	-10.0 (-14.8;-5.0)	< 0.01
AC-CD (%)	-29.0 (-32.0;23.4)	-32.7 (-39.9;26.5)	3.6 (-0.01;9.2)	0.051¹
AC-CT (%)	-6.0 ± 4.9	-11.5 ± 3.5	5.2 (3.2;7.2)	< 0.01
E - early diastolic mitral inflow velocity, A - atrial diastolic mitral inflow velocity, Edt - E wave deceleration time. MD - mean/median differences, CI – confidential interval, IVRT – isovolumetric relaxation time, E’ - early diastolic velocity, A’ - late diastolic velocity. MD - mean/median differences, CI – confidential interval, LAVI – left atrial volume index, AC-CT contractile strain AC-R reservoir strain AC-CD- conduit strain.

ECG assessment.

12-lead electrocardiogram was recorded using BioCare ECG, Reynolds Medical. The morphology of ventricular extra beats, including the QRS duration, bundle branch block pattern, and the axis of the QRS in limb leads, were assessed. Moreover, 24-hour Holter recordings were made using Pathfinder SL, Reynolds Medical system, in which arrhythmia number and burden were registered in the study group. Frequent arrhythmia was defined as a 10% arrhythmia burden in the 24-hour Holter ECG. One cardiologist analyzed the recordings, unaware of the subjects’ other data.

Echocardiography

Conventional transthoracic echocardiography was performed using a Philips EPIQ CVx 5.0

Medical System. Two-dimensional-guided M-mode Tissue Doppler (TDI) and Speckle Tracking echocardiograms were performed in parasternal short axis and apical views. LV end-diastolic dimension (LVDd) and end-systolic dimension (LVSd) were measured at the level of the top of the papillary muscles in M-mode imaging. LVEF, representing LV systolic function, was determined using the Simpson method from 4 chambers and two chambers apical view imaging. The mean value of these measurements was introduced as a result. The normal function was defined as a LVDd within the normal limit (z-score − 2, + 2) and EF 55% or more.

Mitral inflow velocities were obtained from pulsed-wave Doppler in the apical four-chamber view. Early diastolic mitral inflow velocity (E), atrial diastolic mitral inflow velocity (A), and E deceleration time (Edt) of the E wave were measured as diastolic echocardiographic variables. Early diastolic (E’) and late diastolic (A’) velocities were measured at the septal mitral annulus using the tissue doppler imaging method (TDI). The ratio between E and E’ (E/E’) was calculated as an indicator of LV filling pressure. Left atrial volume was evaluated using the biplane area-length method from two orthogonal apical views, as recommended by the American Society of Echocardiography¹⁴. It was indexed to body surface area (LAVI - left atrial volume index). LA function measures were performed using speckle tracking echocardiography with the R–R gating. Three variables were assessed. Firstly, the reservoir strain (AC -R), the first peak between the R wave and the T wave during left ventricular systole, reflects the left atrial filling. Secondly, the conduit strain (AC-CD) reflects the left atrium emptying during the early diastole of the left ventricle. Thirdly, the contractile strain (AC-CT), starting on the P wave, reflects the booster pump function of the left atrium. For each parameter, three consecutive cardiac cycles were averaged, avoiding PVCs. Analysis of echocardiographic data was performed by an investigator who was unaware of the other data in the study and control group.

Cardiopulmonary exercise test (CPET)

All patients performed symptom-limited upright sitting CPET with an incremental RAMP protocol on a bicycle ergometer. After a 3-minute rest period, unloaded paddling was made at a rate of 60 rpm for 2 minutes. The effort was then progressively increased by 10–15 watts/min until the patient could no longer continue a cycling frequency of at least 40 rpm. Cardiopulmonary parameters, such as heart rate, oxygen uptake (VO2) and carbon dioxide production (VCO2), were continuously monitored. Respiratory exchange ratio (RER) (VCO2/VO2) was simultaneously calculated and used to assess maximal effort. The trial ended when the patient could not maintain the pedal cycle rhythm. No study was interrupted due to cardiopulmonary complications. CPETs were considered valid if the VO2 reached a plateau (> 1min) despite increasing workload and/or a complementary respiratory exchange ratio (RER) was ≥ 1.05 combined with the peak heart rate above 85% of predicted. Maximal oxygen uptake (VO2 max) was defined as the oxygen uptake during maximal exercise and was indexed to body weight and time and expressed in milliliters per kilo per minute.

Statistical analysis

Data were analyzed in R 4.0.5. statistical software (R Core Team (2021). R: Language and environment for statistical computing by R Foundation for Statistical Computing, Vienna, Austria). Variables were presented as mean ± standard deviation or median (Q1; Q3), depending on data distribution. Distribution normality was assessed using the Shapiro-Wilk test and based on skewness and kurtosis values and visual assessment of histograms. The study and control group were compared with an independent t-test or Mann-Whitney U test, depending on the data distribution. The data were presented as the mean/median difference (MD), including a 95% confidence interval (CI). Additionally, the correlation between continuous variables was verified with Spearman correlation coefficients. All tests were based on α = 0.05.

All the patients were newly diagnosed with arrhythmia when included in the study. None of them had clinical signs suggesting arrhythmia presence and was not pharmacologically treated when all the tests during the study were performed. The control group consisted of 33 healthy volunteers with normal sinus rhythm in the ECG and 24-hour Holter monitoring. Patients and controls have a similar level of everyday physical activity for up to 3 hours per week.

Rest ECG and 24-hour Holter ECG.

The median number of PVCs for 24 hours was 19976 beats (mean 14823 beats), accounting for 20.5±12.1 % of the arrhythmia burden. In 28 (78%) patients’ inferior axis and in 30 (83%) left bundle branch block morphology of PVC was registered. In 8(22%) and in 6 (17%) of patients superior axis and right bundle branch morphology of PVC were seen, respectively. The mean QRS duration of PVC was 170±21 ms.

Echocardiography

Systolic function.

All the systolic parameters in the study and control group were assessed as normal since they were an inclusion criterion for the study. Table 2.

Diastolic function.

A comparison of the study group vs. controls regarding diastolic and left atrial parameters is summarized in table 3. The analysis revealed a significant difference in E wave deceleration time between PVCs children and healthy volunteers. Evaluation of tissue doppler imaging (TDI) parameters showed significant differences between the study group and controls regarding IVRT and E/E’ ratio. The differences between the study and control groups of left atrial parameters such as LAVI, ECT, and ER, were also statistically significant.

Cardiopulmonary exercise test (CPET)

During CPET patients achieved maximal effort, with RER ≥1,05 and peak heart rate of 85% of the predicted value. The rest heart rate accounted for 94±17 beats per minute and maximal heart rate 186±11 beats per minute. The maximal oxygen uptake (VO2 max) in the study group reached 33.1±6.2 ml/min/kg.

Analysis of diastolic echocardiographic parameters regarding the arrhythmia burden and exercise capacity.

A moderate statistically significant positive correlation was detected between the IVRT and arrhythmia burden (r = 0.49, p < 0.01), Figure 1.

Furthermore, a moderate, negative correlation between maximal oxygen consumption (VO2 max) and E/E’ ratio was detected (r = -0.33, p = 0.02). Figure 2.

The other correlations between the diastolic function parameters and the arrhythmia burden as well as maximal oxygen consumption in the study group were both weak and not significant. Table S1 and S2, supplementary data.

Frequent premature ventricular contractions (PVC) are usually benign. Rarely, they may drive to the contractile dysfunction called “arrhythmic cardiomyopathy.”¹ The risk factors for developing such an entity are defined and listed in the introduction chapter, but the early detection of myocardial function impairment is still challenging. Furthermore, in children, ventricular arrhythmia is usually a primary disease, and the diagnosis of the left ventricular dysfunction before irreversible consequences appear enables proper therapeutic intervention and may substantially improve the prognosis. In our study, we have detected that diastolic function parameters are disturbed, despite the normal left ventricular systolic function, which suggests that diastolic function disturbances precede systolic myocardial impairment in PVC patients.

Among these parameters, the most obvious in children with ventricular arrhythmia was left atrial enlargement and its functional disturbances expressed as strain parameters (reservoir and contractile strain). The left atrial enlargement was already described in adults with PVC in the study of Park Y et al.[⁸, where the indexed left atrial volume correlated statistically significantly with the arrhythmia burden. However, left atrial strain disturbances have not been published so far for adults or children with premature ventricular contractions. In our pediatric population, contrary to the study by Park Y et al., the correlation between arrhythmia burden and left atrial parameters was weak and not statistically significant. There are several explanations for this discrepancy. Firstly, in the cited data, the degree of linear correlation between PVC burden and left atrial size was also not particularly strong despite a larger study population (146 patients) than ours (36 patients). Secondly, the cited trial was performed in a relatively old population (mean age 55 years) compared to ours (mean age 14 years), so left atrial size, reflecting left ventricular filling pressure, may relate not only to PVCs burden but also to the low compliance of the myocardium due to its degeneration what could to some point empower increased filling pressure associated with the ventricular arrhythmia.

The elongation of Edt in our study group suggests that ventricular diastolic dysfunction is at the disease’s initial stage. In general, Edt preservation is closely connected with diastolic function impairment severity. In adults, the elongation of Edt is often seen as a physiological process due to the gradual decline of the myocardial compliance with age, but in young humans reflects early diastolic left ventricular stiffness due to mildly impaired relaxation. Pseudo-normal or mildly reduced Edt is a sign of concomitant concentric left ventricular hypertrophy, and markedly reduced Edt means restrictive filling and advanced diastolic dysfunction.^15,16]

In our patients, the elongation of Edt was probably observed as a reflection of mild relaxation disturbances. We can only speculate that in some patients, during long-term follow-up, the diastolic function would deteriorate further, leading to the irreversible stiffness of the ventricle if proper antiarrhythmic treatment was not performed.

To some point, isovolumetric relaxation time (IVRT) analysis confirms our hypothesis. IVRT was also found to be elongated in our population, which according to our best knowledge, was never described in the literature concerning PVCs in children. Its increase relates to early diastolic dysfunction in many diseases such as hypertrophic cardiomyopathy, arterial hypertension, or diabetes [¹⁷¹⁸ In PVCs children; it is the consequence of dyssynchronous contraction due to arrhythmia, which drives in a natural way to dyssynchronous relaxation. The dyssynchronous myocardial activation is seen not only when a premature beat occurs but also during sinus rhythm neighboring the premature contraction¹⁹. It probably normalizes gradually from beat neighboring to beat remote from PVCs. The evidence for the last assumption does not exist in the literature and needs some further investigation. Still, it could explain why IVRT relates to the arrhythmia burden in our patients.

Another diastolic function parameter disturbed in adolescents with PVCs is E/E’ ratio. It was significantly higher in the cases than in the controls. E/E’ is the primary factor reflecting the filling pressure of the left ventricle, which according to the guidelines, has become one of the most important noninvasive diastolic function parameters.[¹⁶ Our results are concordant with the study of Salem A et al.^7,20 in which it was significantly higher in adults with PVC than in the controls. Moreover, our recent trial found a statistically significant correlation between exercise capacity and E/E’. The elevated filling pressure of the left ventricle is strictly related to the low exercise capacity in many diseases, e.g., aortic stenosis, atrial fibrillation, or diabetes^10–13. Considering such data, we may assume that high E/E’ in children with PVC may reflect increased filling pressure which probably does not normalize during an effort and directly influences exercise capacity. Another possible explanation is that dyssynchronous contraction is the primary factor connected with the low exercise capacity, and the diastolic filling pressure is less meaningful for the exertion tolerance in PVC patients. We can assume that further analysis using detailed hemodynamical evaluation, e.g., stress echocardiography, would help explain the mechanism of low exercise capacity in young individuals with ventricular heart rhythm disturbances.

In conclusion, left ventricular diastolic function is impaired and deteriorates with the arrhythmia burden increase in PVC children. Ventricular arrhythmia in young individuals may be related to exercise capacity decrease due to the left ventricular filling pressure elevation.

Data availability:

A data can be available under reasonable request. If someone wants to request the data from this study a corresponding author Radosław Pietrzak should be contacted; e-mail [email protected]

Author contribution:

RP: conception, design of the work, the acquisition, analysis, interpretation of data;

MF: the acquisition, analysis, interpretation of data, or substantively revision

TMK: design of the work, interpretation of data.

BW: conception, interpretation of data; substantive revision

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No competing interests reported.

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You are reading this latest preprint version

Diastolic function evaluation in children with ventricular arrhythmia.

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

ECG assessment.

Echocardiography

Cardiopulmonary exercise test (CPET)

Statistical analysis

Results

Rest ECG and 24-hour Holter ECG.

Echocardiography

Systolic function.

Diastolic function.

Cardiopulmonary exercise test (CPET)

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1