Reduced Heart Rate Variability May Predict Left Atrial Appendage Thrombus or Spontaneous Echo Contrast in Patients With Non- Valvular Atrial Fibrillation

doi:10.21203/rs.3.rs-2731288/v1

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Research Article

Reduced Heart Rate Variability May Predict Left Atrial Appendage Thrombus or Spontaneous Echo Contrast in Patients With Non- Valvular Atrial Fibrillation

https://doi.org/10.21203/rs.3.rs-2731288/v1

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Objectives

Heart rate variability (HRV) has been associated with cardiovascular disease risk factors and adverse outcomes. Current evidence suggests that the presence of left atrial appendage thrombus (LAAT) or spontaneous echo contrast (SEC) is associated with an increased risk for subsequent stroke in patients with non-valvular atrial fibrillation (NVAF). This study aimed to investigate the relationship between HRV and LAAT/SEC in patients with NVAF.

Methods

347 patients with NVAF treated at Nanfang Hospital in China from Jan 2019 to Dec 2021 were retrospectively analyzed. All patients recruited underwent laboratory evaluation, Transesophageal echocardiography (TEE) and 24h Holter electrocardiography .We explored the differences in demographic, clinical characteristics and HRV parameters between the two groups with and without LAAT/SEC.

Results

In this study, 82 patients (23.6%) had LAAT/SEC. The LAAT/SEC group had lower HRV parameters. After controlling for confounding factors, both SDNN (OR 0.973, 95%CI 0.959–0.987, P < 0.001) and SDANNI (OR 0.985, 95%CI 0.971–0.99, P < 0.001) were found to be independent predictors of LAAT/SEC. Receiver operating characteristic curve analysis revealed that the optimal cutoff value of the SDNN and SDANNI for predicting LAAT/SEC were 132 and 91, respectively. The risk of LAAT/SEC in patients with SDNN ≤ 132 and SDANNI ≤ 91 was 4.064 and 4.083-fold higher than in patients with SDNN > 132 and SDANNI > 91, respectively.

Conclusion

Reduced HRV was inversely correlated with LAAT/SEC in patients with NVAF, suggesting it has huge prospects for clinical application to predict the presence of LAAT/SEC. Early identification and intervention in NVAF patients with decreased HRV may help to decrease the risk of thrombosis.

heart rate variability

left atrial appendage thrombus

spontaneous echo contrast

non-valvular atrial fibrillation

cardiac autonomic function

Atrial fibrillation (AF) is associated with relatively high mortality rates which may be attributed to the increased risk of thromboembolic stroke. Cardioembolic stroke begins with the development of left atrial appendage thrombus (LAAT) in non-valvular atrial fibrillation (NVAF) (1–3). Indeed, it has been established that approximately 90% of thrombi originate from the left atrial appendage (4). There is a growing consensus that Spontaneous Echo Contrast (SEC) is a prethrombotic condition associated with increased risk for subsequent LAAT and stroke in patients with AF(5–8). Transesophageal echocardiography(TEE) is usually performed to exclude thrombi in the left atrium in patients with AF before the procedure. Given its invasive nature, it is not routinely performed for other AF patients during outpatient and follow-up. Accordingly, finding a simple tool to identify patients at risk of developing LAAT or SEC and provide immediate treatment to prevent stroke is critical.

Cardiac autonomic function (CAF) can provide important prognostic information on morbidity and mortality in various cardiovascular diseases and is closely related to the occurrence, maintenance, recurrence and termination of atrial fibrillation(9–12). In recent years, heart rate variability (HRV) analysis has emerged as a valuable noninvasive tool for assessing CAF. AF is considered a limitation of this approach due to the loss of sinus node rhythm. Nevertheless, an increasing body of evidence suggests that the opposite is true. In the Swiss-AF (Swiss Atrial Fibrillation) Cohort Study(13), reduced HRV index was an independent predictor of cardiovascular mortality. Moreover, Frey et al. reported that HRV could quantify diurnal variations in ventricular rate in AF and might be useful in predicting survival in patients with advanced heart failure. In addition, HRV is an independent risk factor for thromboembolic events such as ischemic stroke and myocardial infarction (14–17). It has been recently reported that HRV is independently associated with the presence and volume of silent brain infarcts (18) in patients with AF. There is a rich literature available substantiating that HRV is associated with coagulation and inflammation in several pathological conditions (19–21). However, it remains unclear whether HRV could be a predictor for LAAT/SEC. Therefore, this study aimed to determine the relationship between HRV and LAAT/SEC in patients with NVAF.

2.1 Study Population

Patients with drug-refractory NVAF who underwent TEE and HRV before initial catheter ablation at Nanfang Hospital from Jan 2019 to Dec 2021 were reviewed. Patients were excluded for the following reasons: (1) TEE or HRV results were not available; (2) Acute illness, myocardial infarction, stroke or surgery within 30 days; (3) congestive heart failure with New York Heart Association (NYHA) class III or IV, congenital and structural heart disease, high-grade atrioventricular block, bundle branch block or pacemaker therapy; (4) pregnancy; (5) severe hepatic or renal disease; history of malignancy; uncontrolled hypertension, active thyroid disease, or other life-threatening diseases; or (6) administration of class I, II, or III antiarrhythmic drugs prior to initial heart-rate variability analysis.

The clinical baseline characteristics and medical history were collected from the medical records and analyzed. According to the TEE results, patients were categorized into a LAAT/SEC group and a normal group.

2.2 Echocardiography

Transthoracic echocardiography (TTE) and TEE were performed with the Siemens Acuson ultrasound system (Siemens Medical Solutions USA, Inc.) according to the standards of the American Society of Echocardiography (22, 23). All patients were informed of the detailed procedures before TEE, and written informed consent was obtained. After fasting for at least four hours, topical lidocaine spray was used for local anesthesia. TEE was performed with a unified frequency of a 6.7MHz multiplane probe, and these images were interpreted by experienced echocardiographers. The LA and its appendage were closely inspected for the presence of LAAT and SEC by adjustment of the gain settings to eliminate background noise. LAAT was defined as an echogenic mass in the body of the atrium or the appendage distinct from the adjacent or underlying myocardium. SEC was defined as a presence of dynamic “smokelike” with a slowly swirling. Left ventricular ejection fraction (LVEF) was calculated with the modified Simpson method, and the left atrial dimension (LAD) was measured in the M mode.

2.3 Heart Rate Variability Data

HRV data were recorded over 24-h using a 12-channel Holter monitoring (DMS, DM Software Inc., Stateline, NV, USA) and measured by frequency domain and time domain methods. Because of the fickle ventricular response to random atrial pulses, the time domain was analyzed instead of the frequency domain. All patients underwent a 24-h Holter recording 1–3 days after admission and before the TEE examination and were asked to perform daily activities and refrain from taking any stimulatory foods or drugs during the investigations. The 24-h HRV measurements were conducted according to international guidelines. Time-domain HRV components were analyzed using specialized software (DM Software Inc.).

Six time-domain parameters were measured: 1) the standard deviation of normal-to-normal RR intervals (SDNN); 2) the mean of the standard deviations of normal RR intervals in all 5-min segments (SDNN index, SDNNI); 3) the mean of the standard deviation of the averaged normal-to-normal RR intervals in all 5-min segments (SDANN index, SDANNI); 4) root mean square of successive differences in successive NN intervals (RMSDD); 5) the percent of the differences between the adjacent normal-to-normal intervals > 50 ms (pNN50); 6) heart rate variability triangular index (HRVI). In addition, the mean heart rate (MHR) was recorded.

2.4 Statistical Analysis

Continuous variables were presented as mean ± standard deviation or median (interquartile range), according to whether they were normally distributed or not (Kolmogorov–Smirnov P-values < 0.05). Categorical data were described as frequencies (percentages). Baseline characteristics were compared between groups using the chi-square test, Student-t-test or Mann-Whitney-U-test where appropriate. Correlations among variables were analyzed using Spearman rank correlation for continuous variables and Pearson’s for categorical variables. Logistic regression was used to determine the prediction ability of HRV variables in the LAAT/SEC group after adjusting the variables with a significant association in univariate analysis (P < 0.05). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The receiver operating characteristic (ROC) curve was used to evaluate the efficiency and cutoff of HRV variables for predicting LAAT/SEC in NVAF. The optimal cutoff value for the HRV parameters was determined with the highest Youden index. Given the lack of recognized cutoffs in AF cohorts, we used the observed cutoff value of each parameter for dichotomization. Statistical analysis was performed using the SPSS 26.0 statistical software package. The receiver operating curve (ROC) and the area under the curve (AUC) with the DeLong method of MedCalc software were used. Two-tailed P values < 0.05 were statistically significant.

3.1 General characteristics

The baseline characteristics of the 347 patients enrolled in this study are shown in Table 1. The median age of the study population was 63 (IQR 57–70) years, exhibiting a male predominance (64.3%). The prevalence of LAAT/SEC was 23.6% (n = 82); patients with LAAT/SEC were older and had a greater proportion of non-paroxysmal AF and heart failure, larger LAD, lower LVEF, and higher NT-pro BNP, D-dimer and fibrinogen levels than patients in the normal group. The mean CHA2DS2-VASc-Score was 2.37 ± 1.75 in the normal group and 3.35 ± 1.83 in the LAAT/SEC group.

Table 1

Comparison of basic characteristic between Normal group and LAAT/SEC group
	ALL
Demographics
Female(%)	124(35.7%)	93(35.1%)	31(37.8%)	0.654
Age (y)	63(56.5,70)	62(56–69)	67(59,72)	0.002
BMI (kg/m2)	24.3(21.9,26.2)	24.4(22.1,26.4)	24.27(21.5,25.6)	0.213
Type of AF(%)				0.012
Paroxysmal	152(43.8%)	126(47.5%)	26(31.7%)
Persistent	195(56.2%)	139(52.5%)	56(68.3%)
Duration of AF(months)	12.20 ± 30.62	12.51 ± 32.32	11.21 ± 24.50	0.413
CHA2DS2-VASc	2.6 ± 1.82	2.37 ± 1.75	3.35 ± 1.83	＜0.001
HAS-BLED	1.09 ± 1.02	1.01 ± 1.03	1.35 ± 0.97	0.004
Comorbidities
Heart failure (n,%)	56(16.1%)	27(10.2%)	29(35.4%)	＜0.001
Hypertension (n,%)	184(53%)	137(51.7%)	47(57.3%)	0.373
Diabetes (n,%)	77(22.2%)	59(22.3%)	18(22%)	0.952
CHD (n,%)	55(15.9%)	37(14%)	18(22%)	0.083
Previous stroke (n,%)	67(19.3%)	46(17.4%)	21(25.6%)	0.098
Results of inspection
Creatinine(umol/L)	80.31 ± 14.17	80.11 ± 14.5	80.96 ± 13.11	0.634
GFR(ml·min^− 1·1.73 m^− 2)	81.15(71.09,96.67)	81.98(72.43,97.62)	77.86(68.47,90.36)	0.077
NT-pro BNP(pg/ml)	723.1(235.95,1486.19)	437.15(153.2,1065.5)	1486.19(718.8,2690)	＜0.001
Triglycerides(mmol/L)	1.31(0.96,1.96)	1.33(0.95,1.97)	1.25(0.98,1.88)	0.562
Cholesterol(mmol/L)	4.38(3.62,5.25)	4.44(3.67,5.25)	4.14(3.43,5.28)	0.653
Fibrinogen(g/L)	3.06(2.55,3.52)	3.01(2.54,3.44)	3.17(2.77,4.06)	0.012
D-dimer(ug/ml)	0.33(0.19,0.63)	0.31(0.18,0.63)	0.47(0.22,0.93)	0.004
LAD(mm)	40.81(36,44)	40(36,43)	42(39,47)	＜0.001
LVEF (%)	59.34(56.4,64.42)	60.61(57.42,65.06)	57.32(50.72,60)	＜0.001
anticoagulants(n,%)	180(51.9%)	140(25.8%)	40(48.8%)	0.521
BMI body mass index, CHD coronary heart disease, GFR glomerular filtration rate, LAD left atrial dimension, LVEF left ventricular ejection fraction, AADs antiarrhythmic drugs.
All patients had a diagnosis of non-valvular atrial fibrillation. Data are means ± SD or counts (percentages)
p value compares normal and LAAT/SEC groups and were obtained from Student’s t tests or Mann-Whitney U test for continuous variables and chi-square tests for categorical variables

3.2 HRV and Left Atrial Appendage Thrombus/Spontaneous Echo Contrast

Table 2 shows the results of time domain measures of HRV in the LAAT/SEC group and the normal group. Medians (range) of HRV parameters were as follows: MHR 81ms (69–92 ms), SDNN 156 ms (129–184 ms), SDANNI 89 (67.5–119 ), SDNNI 116 (81–147 ), rMSSD 131 ms (82.5–167 ms), pNN50 67 (29–76%) and HRVI 36.7 (29.3–44.7); all were asymmetrically distributed (Kolmogorov-Smirnov P-values < 0.05). The LAAT/SEC group had lower SDNN and SDANNI (P < 0.001) and lower SDNNI (P = 0.012) than normal group patients, while the rMSSD and pNN50 were comparable. MHR was faster in the LAAT/SEC group (P < 0.001). Measures of HRV showed significant but weak correlations with clinical variables of this study (Table 4).

Table 2

Comparison of HRV parameters between Normal group and LAAT/SEC group
	ALL	Normal group(265)	LAAT/SEC group(82)	P-value(univariate analysis)
MHR(bpm)	81(69,92)	78（68,89）	84（76,102）	＜0.001
SDNN(ms)	156（129,184)	166(137,191)	122（102,152）	＜0.001
SDANNI	89(67.5,119)	101(74,130)	63（48,85）	＜0.001
SDNNI	116(81,147)	123(79,149)	103.5（84,128）	0.012
rMSSD(ms)	131(82.5,167)	134(66,177)	116.5（90,152）	0.248
pNN50(%)	67(29,76)	68(22,77)	67（60,72）	0.911
HRVI	36.7（29.3,44.7）	38.4（31.4,46.1）	31.75(25.7,38.7）	＜0.001
SDNN＜132	102(29.4b％)	52(19.6％)	50(61％）	＜0.001
SDANNI＜91	179(51.6％）	109（41.1％）	70(85.4％)	＜0.001
MHR mean heart rate, SDNN the standard deviation of normal-to-normal RR intervals, SDANNI (SDANN index)the mean of the standard deviation of the averaged normal-to-normal RR intervals in all 5-min segments, SDNNI(SDNN index) the mean of the standard deviations of normal RR intervals in all 5-min segments, RMSDD root mean square of successive differences in successive NN intervals, pNN50 the percent of the differences between the adjacent normal-to-normal intervals >50 ms, HRVI heart rate variability triangular index. Data are medians and interquartile range p value compares between two groups and was obtained from Mann–Whitney-Test

3.3 Predictors of Left Atrial Appendage Thrombus/Spontaneous Echo Contrast

During multivariate regression analysis(Table 3), we excluded SDNNI from models because of collinearity. SDNN and SDANNI were independent predictors of LAAT/SEC (for SDNN: OR 0.970, 95%CI 0.958–0.984, P < 0.001, for SDANNI: OR 0.985, 95%CI 0.971–0.99, P = 0.049; Table 2). In addition, larger LAD and lower LVEF showed a positive correlation with increased LAAT/SEC(Fig. 1). ROC curve analysis was used to evaluate the relationship between SDNN, SDANNI and LAAT/ SEC. The area under the curve (AUC) of SDNN for predicting LAAT/SEC was 0.784 (95%CI: 0.737–0.826, P < 0.001); a cutoff value of 132 yielded a specificity of 80.38% and a sensitivity of 60.98%. For SDANNI, the AUC was 0.791 (95%CI: 0.745–0.833, P < 0.001), and a cutoff value of 91 predicted the left atrial blood stasis with a specificity of 58.87% and a sensitivity of 85.37%. Multivariate logistic regression showed that SDNN ≤ 132 and SDANNI ≤ 91 were independently associated with LAAT/SEC (for SDNN ≤ 132: OR 4.064, 95%CI 2.014–8.201, P < 0.001, for SDANNI ≤ 91: OR 4.083, 95%CI 1.82–9.161, P = 0.001; Table 3).

Table 3

Risk of LAAT or SEC in multivariate analysis
Variable	Multivariate model 1^a		Multivariate model 2^b
Variable	P-value	OR (95% CI)	P-value	OR (95% CI)
Age	0.774	1.006(0.964,1.05)	0.738	1.007(0.966,1.05)
Type of AF	0.84	0.924(0.427,1.997)	0.644	0.838(0.396,1.774)
CHA2DS2-VASc	0.44	1.114(0.847,1.464)	0.495	1.101(0.836,1.45)
HAS-BLED	0.97	0.992(0.664,1.484)	0.977	0.994(0.66,1.498)
Heart Failure	0.768	1.138(0.482,2.691)	0.778	0.884(0.376,2.08)
NT-pro BNP	0.143	1(0.99,1.00)	0.102	1(0.99,1)
Fibrinogen	0.257	1.195(0.879,1.625)	0.38	1.147(0.845,1.556)
D-dimer	0.401	1.152(0.829,1.6)	0.211	1.233(0.888,1.713)
LAD	0.012	1.062(1.013,1.114)	0.016	1.059(1.011,1.11)
LVEF	0.022	0.95(0.91–0.993)	0.008	0.943(0.902,0.985)
MHR	0.104	0.992(0.972,1.013)	0.469	0.993(0.973,1.013)
SDNN	＜0.001	0.973(0.959,0.987)	-	-
SDANNI	0.049	0.985(0.971,0.99)	-	-
HRVI	0.735	1.007(0.967,1.049)	0.241	0.98(0.947,1.014)
SDNN ≤ 132	-	-	＜0.001	4.064(2.014,8.201)
SDANNI ≤ 91	-	-	0.001	4.083(1.82,9.161)
LAD left atrial dimension, LVEF left ventricular ejection fraction, MHR mean heart rate, SDNN the standard deviation of normal-to-normal RR intervals, SDANNI (SDANN index) the mean of the standard deviation of the averaged normal-to-normal RR intervals in all 5-min segments, HRVI heart rate variability triangular index
^aMultivariate model 1: including age, Type of AF, CHA2DS2-VASc score, HAS-BLED score, Heart Failure, NT-pro BNP, Fibrinogen, D-dimer, LAD, LVEF, NLR, MHR, HRVI, SDNN and SDANNI.
^bMultivariate model 2: including age, Type of AF, CHA2DS2-VASc score, HAS-BLED score, Heart Failure, NT-pro BNP, Fibrinogen, D-dimer, LAD, LVEF, NLR, MHR, HRVI, SDNN ≤ 132 and SDANNI ≤ 91.

Table 4

Correlation between heart rate variability measures and clinical features
	SDNN	SDANNI	HRVI	MHR
SDNN	-	0.589^**	0.610^**	-0.297^**
SDANNI	0.589^**	-	0.361^**	-0.437^**
HRVI	0.610^**	0.361^**	-	-0.302^**
MHR	-0.297^**	-0.437^**	-0.302^**	-
Age	-0.118^*	-0.201^*	-0.111^*	0.031
Type of AF	-0.034	-0.420^**	0.079	0.315^**
CHA2DS2-VASc	-0.194^**	-0.274^**	-0.146^**	0.110^*
HAS-BLED	-0.156^**	-0.177^**	-0.141^**	0.062
Heart Failure	-0.224^**	-0.266^**	-0.246^**	0.293^**
NT-pro BNP	-0.192^**	-0.459^**	-0.151^**	0.368^**
Fibrinogen	-0.120^*	-0.224^**	-0.152^**	0.152^**
D-dimer	-0.210^**	-0.247^**	-0.199^**	0.182^**
LAD	-0.049	-0.306^**	-0.044	0.250^**
LVEF	0.084	0.264^**	0.120^*	-0.321^**
Data represent Spearman`s rank correlation coefficient or Pearson’s correlation.
LAD left atrial dimension, LVEF left ventricular ejection fraction, MHR mean heart rate, SDNN the standard deviation of normal-to-normal RR intervals, SDANNI (SDANN index) the mean of the standard deviation of the averaged normal-to-normal RR intervals in all 5-min segments, HRVI heart rate variability triangular index
p < 0.05, *p < 0.01

The present study provided hitherto undocumented evidence of the association between HRV and LAAT/SEC in patients with NVAF. Our results substantiated that lower HRV is independently associated with the risk of LAA thrombogenic milieu in NVAF. The risk of LAAT/SEC in patients with SDNN ≤ 132 and SDANNI ≤ 91 was 4.064 and 4.083-fold higher in patients with SDNN > 132 and SDANNI > 91, respectively.

It is well-established that the pulmonary veins are critically important in initiating AF (24, 25). Once activated, AF can lead to atrial remodeling through changes in electrical and structural properties of the atria and thus facilitate maintenance and recurrence of AF(26, 27). However, the mechanisms underlying the development of ectopic lesions in PVs remain unclear. Since the pulmonary vein and the pulmonary vein-left atrium junction are histologically rich in sympathetic and parasympathetic nerves, paroxysmal discharge of the CAF is widely thought to be a possible mechanism. It has been reported that the ablation of these intrinsic cardiac nerves suppresses or eliminates focal AF from pulmonary veins, supporting a causal relationship between CAF activity and AF(28). Many studies used HRV parameters to estimate the dysfunction of CAF. HRV is a quantitative measure of the balance between the sympathetic and parasympathetic nervous systems. Most studies that assessed sinus node rhythm disorders using HRV excluded AF patients. However, it should be borne in mind that the atria are rich in autonomic innervation, and these nerves can still modulate HRV in AF through the atrioventricular node, which is susceptible to autonomic input(29). Overwhelming evidence substantiates that lower HRV is associated with an increased risk of new-onset AF(30–32). In addition, Peter et al. found that HRV was independently associated with the presence and volume of silent brain infarcts in patients with AF (18) and was also an independent predictor of cardiovascular mortality (13). The above studies indicate that HRV is also applicable in patients with AF and may provide reliable prognostic information for the occurrence and development of AF.

Herein, we demonstrated that impaired HRV is associated with thromboembolic events, consistent with the literature. A previous study has identified an association between low HRV and the risk of all-cause mortality and cardiovascular mortality in older stroke survivors(14). In the Atherosclerosis Risk In Communities (ARIC) study, a lower HRV was associated with a higher risk of incident stroke among middle-aged adults with prevalent diabetes (15). Amber et al. found an independent association between low nighttime HRV and increased risk of incident ischemic stroke after adjustment of conventional risk factors (16). It has been reported that HRV is independently associated with the presence and volume of silent brain infarcts in AF patients (18). Eiichi et al. (33)indicated that multiscale entropy, a novel complexity measurement of the HRV, was a useful risk stratification measure of ischemic strokes in patients with permanent AF, but this method requires a more complex machine and calculation formula. The mechanisms underlying the relationship between lower HRV and stroke remain largely unknown. In this study, we found that lower HRV was independently associated with the presence of LAAT/SEC in patients with NVAF, which suggested that lower HRV increases the risk of thromboembolism in patients with NVAF.

The mechanism of how HRV affects LAAT/SEC remains largely obscure. HRV is a cardiovascular risk marker associated with inflammation (34, 35), which can reportedly drive a thrombotic state. It has been shown that reduced HRV is associated with reduced parasympathetic activity, which may enhance hypercoagulation or increase blood viscosity (19, 21). Hamaad et al.(19) consistently reported that lower HRV is associated with markers of hemostasis and thrombosis in Acute Coronary Syndrome. Increased inflammation and coagulation have often been associated with the development of LAAT/SEC (36, 37). Given that lower HRV is also associated with these factors, it might reflect an increased propensity for inflammatory and coagulation disorders in patients predisposed to develop LAAT/SEC. In addition, impairment of the CAF and the consequent sinus node disorder may enhance wall stress in the atrium, which may induce episodes of paroxysmal atrial fibrillation and even a tendency toward thromboembolism (38). Overall, a decreased HRV may cause hypercoagulation and more disturbed left atrial hemodynamics, which may lead to the formation of LAAT/SEC.

Among the time domain parameters of HRV, SDNN and SDANNI reflect both sympathetic and parasympathetic modulation, and lower SDNN and SDANNI indicate a relative sympathetic predominance (6). No difference was found between LAAT/SEC and the vagally mediated indices of rMSSD and pNN50, suggesting the inverse correlation between LAAT/SEC and SDNN and SDANNI is mainly due to enhanced sympathetic activity. The SDNN is the most commonly used parameter. A previous literature review reported that compared to other measures of HRV, the SDNN showed the strongest and most robust negative associations with inflammatory markers like CRP, Il-6, and WBC(20). The Copenhagen Holter study, which comprised 678 healthy persons between the ages of 65 and 75, indicated that nighttime SDNN was significantly connected with stroke in the follow-up period (16). The SDNN can reflect all changes in the heart period, whereas SDANNI reflects alterations that take place over long periods. The SDANNI behaves much like SDNN, suggesting that much of it may change similarly.

There were several limitations in this study. First, it should be borne in mind that the severity of SEC could be affected by ultrasound system controls. However, we graded SEC as present or absent to reduce observation error. Besides, we did not exclude patients on anticoagulant medication since these patients still had a high prevalence of LAAT/SEC in this study. Accordingly, the HRV measures can also predict LAAT/SEC in patients on anticoagulant drugs. Finally, as our study was a small single-center cross-sectional study, the causal relationship could not be established. In addition, we did not determine if HRV was merely a marker or a mediator of LA thrombus in patients with NVAF. Indeed, prospective studies with large sample sizes are warranted to validate the relationship between HRV and LAAT/SEC.

This study provided hitherto unreported evidence of the association between HRV and LAAT/SEC in patients with NVAF. A lower HRV indicated increased susceptibility to LAAT/SEC in NVAF patients, and SDNN and SDANNI were ideal HRV parameters to predict LAAT/SEC. Accordingly, early screening and intervention in AF patients with decreased HRV may help to prevent thrombosis and improve patient outcomes.

Ethics approval and consent to participate

All methods in this study were carried out in accordance with the Declaration of Helsinki. The Ethics Committee of Southern Medical University approved the study protocols and waved the need for informed consent due to the retrospective collection of anonymized clinical data.

Consent for publication

This study does not contain any individual person’s information or images.

Availability of data and materials

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

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This research was supported by the Clinical Research Startup Program of Southern Medical University of High-level University Construction Funding of Guangdong Provincial Department of Education (LC2016ZD002).

Acknowledgments

We wish to acknowledge all the patients in this study

Author Contributions

MY, ZL and XG designed the study and drafted the manuscript and did the statistical analysis. HZ , XY and JO collected patient data , YT edited the images. LH and SZ revised the manuscript. JP critically revised the manuscript and approved the article. All authors contributed to the article and approved the submitted version.

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No competing interests reported.

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Reduced Heart Rate Variability May Predict Left Atrial Appendage Thrombus or Spontaneous Echo Contrast in Patients With Non- Valvular Atrial Fibrillation

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Abstract

Objectives

Methods

Results

Conclusion

Figures

1 Introduction

2 Method

2.1 Study Population

2.2 Echocardiography

2.3 Heart Rate Variability Data

2.4 Statistical Analysis

3 Results

3.1 General characteristics

3.2 HRV and Left Atrial Appendage Thrombus/Spontaneous Echo Contrast

3.3 Predictors of Left Atrial Appendage Thrombus/Spontaneous Echo Contrast

4 Discussion

5 Limitations

6 Conclusions

7 Declarations

References

Additional Declarations

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