Triglicerydes/high‐density lipoprotein ratio as a risk factor of post‐Covid‐19 sinus tachycardia: A retrospective study

Inappropriate sinus tachycardia (IST) is one of the manifestations of the post‐COVID‐19 syndrome (PCS), which pathogenesis remains largely unknown. This study aimed to identify potential risk factors for IST in individuals with PCS. The 1349 patients with PCS were included into the study. Clinical examination, 24H Holter ECG, 24H ambulatory blood pressure monitoring and biochemical tests were performed 12–16 weeks after the COVID‐19 in all participants. IST was found in 69 (3.5%) individuals. In the clinical assessment IST patients were characterized by a higher age (p < 0.001) and lower prevalence of the diagnosed hypertension (p = 0.012), compared to remaining patients. Biochemical testing showed higher serum triglycerides (1.66 vs. 1.31 pmol/L, p = 0.007) and higher prevalence of a low high‐density lipoprotein (HDL) cholesterol (24.6% vs. 15.2%, p = 0.035) in the IST group. Subsequently, the triglicerydes (TG)/HDL ratio, an indicator of insulin resistance, was significantly higher in the IST individuals (3.2 vs. 2.4, p = 0.005). 24H monitoring revealed a significantly higher minimum diastolic, maximum systolic and mean arterial blood pressure values in the IST group (p < 0.001 for all), suggesting a high prevalence of undiagnosed hypertension. A multivariate analysis confirmed the predictive value TG/HDL ratio >3 (OR 2.67, p < 0.001) as predictors of IST development. A receiver operating characteristic curve analysis of the relationship between the TG/HDL ratio and the IST risk showed that the predictive cut‐off point for this parameter was 2.46 (area under the ROC curve = 0.600, p = 0.004). Based on these findings, one can conclude that insulin resistance seems to be a risk factor of IST, a common component of PCS.

Word Health Organization statistics report that almost 800 million people have been infected with SARS-CoV-2 worldwide since 2019.
Although the pandemic is estimated to have caused nearly 700 000 deaths, most of those infected had mild symptoms and did not require hospitalization. 1 However, up to 40% of SARS-CoV-2infected individuals complain of persisting or new-onset symptoms in the longer course, which is referred to as to ongoing symptomatic COVID-19 (post-acute COVID- 19) or post-COVID-19 (long COVID) syndrome (PCS) when remnant symptoms persist from 4 to 12 weeks and for more than 12 weeks, respectively. 2e PCS (or long COVID) term covers a number of complaints including symptoms of prolonged infection (e.g., headache, joint/ muscle pain, dizziness, fever, shortness of breath, dry cough, sneezing) as well as a plethora of signs not associated with past infection (e.g., neurocognitive disorder or altered sleep structure). 3mited understanding of the pathological mechanisms underlying PCS represents a critical challenge to effectively identify and treat the affected individuals.
One of the PCS manifestations is the injury to the autonomic nervous system (ANS), believed to be responsible for many symptoms such as orthostatic hypotension, postural orthostatic tachycardia syndrome, chest pain, and cardiac arrhythmias, including inappropriate sinus tachycardia (IST). 4,5IST is defined by a sinus heart rate inexplicably higher than one hundred beats per minute (bpm) at rest that is associated with symptoms like palpitations, dyspnea or dizziness in the absence of primary causes of tachycardia. 6,7Potential causes of IST include: sympathovagal imbalance, beta-adrenergic receptor hypersensitivity, and brain stem dysregulation leading to the hypoactivity of the parasympathetic tone; however its pathogenesis is not fully understood. 8,9e aim of the present study was to perform a thorough clinical characterization of patients with IST to identify potential risk factors for this arrhythmia in individuals with PCS.

| Study design
This was a retrospective study based on an analysis of data from 1349 patients in the STOP COVID registry (PoLoCOV [identifier ClinicalTrials.gov-NCT05018052]).The STOP COVID registry contains medical information on patients from Poland presenting to health centers from 1 September 2020 to 30 September 2021 with persistent clinical symptoms after COVID-19 and subsequent followup visits at 3 months (as described previously). 10e inclusion criteria for the study were as follows: (i) diagnosis  1).The use of this method to assess the severity of COVID-19 infection was due to the fact that the majority of diagnoses (n = 1139) were made by remote contact with a physician and there were no qualified medical personnel available to assess the severity of the disease at the time of diagnosis.
The following symptoms of long-term COVID-19 infection were assessed: cough, dyspnea, chronic fatigue, alopecia, olfactory  All patients were ordered the twenty-4 h ABPM and the following mean values were analysed: minimum blood pressure (minimum BP), maximum blood pressure (maximum BP) and average blood pressure (average BP).Additionally the numbers of patients with systolic blood pressure(SBP) ≥ 130 mmHg and diastolic blood pressure (DBP) ≥ 80 [mmHg] were compared between the studied groups.

| Echocardiography
Echocardiography was performed by a specialist-a cardiologist-according to the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) recommendations. 15rasternal and apical projections (four-chamber, three-chamber and

| Biochemical testing
At the first visit, 5 mL of venous blood was taken from the patients and, after centrifugation, the concentrations of the following parameters were determined: total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, non-HDL cholesterol, glucose.Subsequently, triglicerydes to HDL cholesterol index (TG/HDL) as an indicator of insulin resistance was calculated.An index value of > 3 was considered the cut-off point for the diagnosis of insulin resistance. 16e study was conducted in accordance with the tenets of the Declaration of Helsinki and approved by the Bioethics Committee of the Medical University of Wroclaw (approval number 232/2022).

| Statistical analysis
The variables analysed were qualitative and quantitative.Normally distributed continuous variables were compared using Student's t-test, while the Mann-Whitney U test was used in the case of variables without normal distribution.Assessment of the normality of the distribution was performed using the Shapiro-Wilk test.For qualitative variables, the Chisquare test was performed, while for quantitative variables, the nonparametric Mann-Whitney U test.Univariate logistic regression analysis was used to assess risk factors for the development of IST, and the dependent variable was the prevalence of IST and the independent variables were socio-demographic data, chronic conditions, COVID-19 course and outcome analysis.A complex logistic regression analysis model was then built using backward stepwise analysis.In the model built, the dependent variable was the prevalence of IST and the independent variables were age, gender, BMI, hypertension, diabetes mellitus, hyperlipidaemia, asthma, COPD, hospitalization for COVID-  Inappropriate sinus tachycardia (IST) was found in 69 (

| Biochemical characteristics of patients with inappropriate sinus tachycardia
Analysis of laboratory tests (Table 3) showed that the most common abnormality in the whole study group was excessively high total cholesterol (53.4%) and non-HDL cholesterol (58.0%).Stratification of the study participants according to the prevalence of IST revealed, that patients with IST, compared to those who did not experienced this arrythmia, were significantly more likely to have excessively high triglycerides (36.2% vs 21.7%, p = 0.004) and abnormal, low HDL cholesterol values (24.6% vs. 15.2%,p = 0.035).Subsequently, in patients with IST the TG/HDL ratio (3.2 ± 3.1 vs. 2.4 ± 1.9, p = 0.005) was higher and a higher was the proportion of individuals with TG/ HDL ratio >3 (36.2% vs. 1.5%, p < 0.001), which is a cut-off point suggestive of insulin resistance.

| ABPM, Holter ECG and echocardiography findings in of patients with inappropriate sinus tachycardia
The analysis of ABPM results showed that patients with IST, compared to those who did not experienced this arythmia reached significantly higher minimum diastolic (p < 0.001), maximum systolic In addition, since organic heart disease may predispose to tachyarrhythmias, echocardiography was performed in 1034 study participants (53 with a diagnosis of IST and 981 without this diagnosis).Patients with a diagnosis of IST had significantly smaller aortic width (29.1 mm ± 3.1 vs. 30.9mm ± 3.9, p < 0.001), IV systole (12.9 mm ± 1.6 vs. 13.3 mm ± 1.4, p = 0.044) and dimensions of the left atrium (36.8 mm ± 4.7 vs. 38.6 mm ± 4.8, p = 0.012) and right ventricle (26.9 mm ± 2.8 vs. 28.4mm ± 3.6, p = 0.002).Importantly, there was no significant difference in ejection fraction of left ventricle and the incidence of myocardial hypo/akinesis between the groups compared (Supporting Information S1: Table S1).

| Analysis of inappropriate sinus tachycardia risk factors
In univariate analysis, the risk of developing IST was shown to be associated with high triglycerides concentration (OR 2.04, p = 0.005).
IST was also found to be significantly more common in patients with a TG/HDL ratio >3 (OR 2.08, p = 0.003), which, as previously mentioned, is a cut-off point suggestive of insulin resistance.In contrast, a potentially protective factor was age (OR 0.96, p = 0.001).
A detailed summary of the univariate analysis of inappropriate sinus tachycardia risk factors is presented in Table 5.
A multivariate analysis confirmed the predictive value of SBP ≥ 130 (OR = 2.07, p = 0.006) TG/HDL ratio >3 (OR = 2.67, p < 0.001) as predictors of IST development.It pointed out also at age as a protective factor (OR = 0.95, p < 0.001).What was new was the evidence that female gender could be a risk factor for IST (OR = 2.35, p = 0.004).A summary of the results of the multivariate analysis is presented in Table 6.
A receiver operating characteristic (ROC) curve analysis of the relationship between the TG/HDL ratio and the risk of developing IST (Figure 1) showed that the cut-off point for the risk of developing IST was 2.46 (area under the ROC curve = 0.600 [0.531, 0.668], p = 0.004).Figure 2.

| DISCUSSION
The COVID-19 pandemic has permanently changed everyday life.Note: Significant differences (p < 0.05) were marked with bold characters.
F I G U R E 2 ROC curve analysis of the relationship between the TG/HDL ratio and the risk of developing inappropriate sinus tachycardia.
4][5] This paper sought to identify potential factors that predispose patients to develop IST after COVID-19.A retrospective analysis of 1,349 individuals from the STOP COVID registry revealed that IST was significantly more common in patients with an elevated TG/HDL ratio, an indicator of insulin resistance.
The incidence of IST in the study cohort was 3.5%, which is lower compared to the incidence observed in a previous study performed by Aranyó et al., who found this arrythmia in 20% of patients with PCS. 17 However, it should be noted that the cohort studied in that paper consisted of 200 patients, more than six times fewer than in the present study, which increases the likelihood of a type 2 statistical error.This argument seems to be valid given the fact that in study conducted in larger groups of patients with PCS, the incidence of tachyarrhythmias has been estimated to be less than 9%. 18It should also be noted that the reason for the difference in the incidence of IST could be the criteria used to diagnose this tachyarrhythmia.In our study, 24-h Holter ECG monitoring was decisive, whereas in the paper by Aranyó, J et al., resting ECG.
Compared to the other study participants, patients with IST were characterized by older age and a higher prevalence of obesity, while in the biochemical parameters assessed-by higher mean triglyceride (TG) concentrations with lower mean HDL cholesterol levels.All these factors contribute to a higher cardiometabolic risk.Only one element did not fit this picture-the rarer prevalence of diagnosed hypertension in the group with IST compared with other patients with PCS.However, the 24-month monitoring showed significantly higher maximum, minimum and mean blood pressure values in this group.Moreover, the individuals with IST were was significantly more likely to have an elevated systolic blood pressure.This suggests that a significant proportion of hypertensive cases in the IST group remained undiagnosed and therefore untreated, increasing the cardiometabolic risk in these patients. 19RYŁOWICZ ET AL.
| 7 of 10 Obesity is considered as a risk factor for tachyarrhythmias.A higher body weight predisposes to a higher baseline and exertional heart rate with a prolonged recovery which is a predictor of cardiovascular risk and cardiovascular mortality. 20Autonomic nervous system (ANS) dysfunction due to sympathetic overactivity is recognized as a cause of an alteration in cardiac repolarization times in obese individuals. 21Both basic and clinical research point to impaired insulin sensitivity as a mechanism linking ANS with obesity, due to the inotropic effects of insulin. 22,23wever, the relation between the ANS dysfunction and insulin resistance can be bidirectional as sympathetic overactivity impairs peripheral glucose uptake in skeletal muscle by inducing vasoconstriction and reducing skeletal muscle blood flow. 24Moreover, sympathetic overactivity leads also to the stimulation of the renin-angiotensinaldosterone system that contributes to the in insulin resistance. 25spite the complex interaction between ANS and insulin resistance and difficulty to determine which phenomenon-insulin resistance or ANS overactivity-is primary, this association is unquestionable.In addition, insulin resistance is a recognized factor in increasing the risk of cardiovascular disease. 26Therefore, in searching for factors that predispose patients with PCS to the development of IST, the indicators of insulin resistance have been analysed.As fasting insulin measurements are subject to a high risk of prelaboratory error and are often underpowered in population studies, the choice was made for the TG/ HDL ratio. 27This parameter is known as a powerful indicator for coronary heart disease, but, given the involvement of insulin in lipid metabolism, also quite accurately reflects the impaired insulin sensitivity. 28It turned out, that in the studied cohort, the mean TG/HDL ratio value was significantly higher in patients diagnosed with IST, compared to the rest of the studied population.Moreover, in the individuals with IST, the TG/ HDL > 3 (which is suggested as cut-off value for insulin resistance) was significantly more prevalent.However, as there is no clear consensus on the cut-off point for the TG/HDL ratio as a predictor of insulin resistance, a ROC curve analysis of the relationship between the TG/HDL ratio and the risk of developing IST was performed.This analysis indicated that the cut-off point for the risk of developing IST in the studied cohort was 2.46.This is undoubtedly a novel observation, even though, the sensitivity of the TG/HDL ratio may be population specific, for example, it does not work well as a predictor of cardio-metabolic risk in African Americans.
Independently, a recent prospective study demonstrated a clear relationship between elevated TG/HDL levels (as well as elevated triglyceride/glucose index) and insulin resistance as a predictor of progression from prediabetes to diabetes. 29This finding is of value because a meta-analysis indicated the high frequency of new-onset diabetes in long-COVID-19 patients, with risks ranging from 11% to 276% compared with patients. 30Further research is needed to explain why only 3.5% of all potential patients with a potential worsening insulin resistance after COVID-19 develop IST.Our findings demonstrated that this is not the group with coexisting organic heart disease.
In discussing the findings, the potential limitations of the study have to be mentioned, resulting, for instance from its design.First, the retrospective nature of our study may have introduced a number of biases and, for example, precluded the analysis of other symptoms of autonomic dysfunction.An analysis of the occurrence of other signs of autonomic dysfunction, such as orthostatic hypotension (OH) or vasovagal syncope (VVS), would have provided a more complete picture of the impact of a history of COVID-19 infection on autonomic function.Next, although we included in the exclusion criteria those conditions that could cause autonomic dysfunction independently of COVIID-19 infection, we could not exclude the effect of certain drugs (e.g., betamimetics) on the occurrence of sinus tachycardia."Moreover, the choice of the TG/HDL ratio as a marker of insulin resistance may be questionable.However, there is currently no consensus on a reliable predictor of reduced insulin sensitivity for routine use in screening.The hyperinsulinaemic euglycaemic clamp, which is the gold standard, is not applicable in this context due to the difficulty of implementation.Simpler indices such as HOMA-IR require fasting insulin, which is associated with a high risk of prelaboratory error due to the instability of this hormone.Epidemiological studies suggest that the TG/HDL ratio, although not a direct measure of insulin resistance, correlates well with insulin sensitivity and cardiometabolic risk. 31As waist circumference was not measured in all study participants, it was not possible to assess the prevalence of metabolic syndrome in our cohort and its impact on TG/HDL levels. 32Another issue is the purely descriptive nature of the results and the fact that, without investigating the pathomechanisms in detail, we can only describe a correlation between the insulin resistance indicator and IST and assume that it has a causal relationship.However, we know from both basic and clinical research that insulin resistance-associated hyperinsulinaemia increases the excessive sympathetic activation. 23,33It should also be noted that no differential diagnosis of the causes of IST or screening, for example for anxiety disorders or hyperthyroidism as a possible cause of the reported symptoms, was performed in the study group.Finally, no data were collected on the medications used by the study participants before COVID-19 infection, so it is not clear how many of them were taking medications that affect heart rate or lipid levels.
It is therefore possible that the prevalence of IST in the study group was even higher than observed, and the inclusion of patients with IST masked by medication would have affected the results obtained.
Despite the limitations mentioned above, the present study also has undeniable strengths.These include the large number of well clinically characterized participants, which ensures the power and reliability of the results obtained, and the fact that all individuals had a 24 h ECG Holter monitoring performed, which is a sensitive and recommended method for IST detection.

| CONCLUSIONS
In conclusion, based on this study findings, elevated insulin resistance indices seem to be risk factors to development of inappropriate sinus tachycardia, a common component of post-COVID-19 syndrome.One possible mechanism linking insulin resistance and IST is a stimulating impact of hyperinsulinemia on sympathetic nervous system activity, although this hypothesis needs to be verified in basic research.
of COVID-19 (by a reverse transcription-polymerase chain reaction (PCR) test and/or an antigen test); (ii) age ≥18 years; (iii) written informed consent to participation in the study.Exclusion criteria included (i) age <18 years; (ii) lack of consent to participation in the study, (iii) chronic conditions such as heart failure, coronary heart disease, post-myocardial infarction status, cardiomyopathy and irreversible causes of tachycardia (to exclude patients from the study group who may have other causes of the symptom being analyzed).In addition, patients with with a history of hyperthyroidism and TSH below the reference range were not included in the study.All study participants, before enrollment, were informed of the study objectives and methodology, and gave informed consent to participate in the study.At each visit, patients completed health questionnaires regarding persistent symptoms up to 3 months after isolation and underwent a physical examination.At the first visit, patients provided their sociodemographic data, medical history of chronic diseases and medication use, clinical symptoms experienced during COVID-19 and their duration as well as places of isolation.The list of acute COVID-19 symptoms assessed included fever (body temperature >38.0 • C), subfebrile state (body temperature 37.0-38.0• C), chills, cough, headache, myalgia, weakness, dyspnea (subjective), smell/taste/hearing disturbance and chest pain.The patient then gave a subjective rating on a four-point scale of the perceived severity of the COVID-19 course.Based on all of the above data, the severity of the COVID-19 course was rated on a four-point scale (Table two-chamber) were recorded during the study.An additional modified apical projection of the right ventricle.Based on the projections, the contractility of the left and right ventricles was analyzed.In the evaluation of the left ventricle, end-systolic and end-diastolic volumes and left ventricular ejection fraction (EF) were measured.Pulmonary flow and transvalvular flow were also assessed.Assessment of the right ventricular systolic function was based on the evaluation of the tricuspid annular systolic excursion amplitude (TAPSE) and the measurement of the maximum myocardial systolic velocity S' of the tricuspid annulus/basal segment of the RV free wall, established using tissue echocardiography (TDE).

3 | RESULTS 3 . 1 |
Prevalence of the inappropriate sinus tachycardia in the studied group and clinical characteristics of the affected individuals Initially, 3391 patients were enrolled in the study, of whom 427 did not attend a follow-up visit.Of the 2964 patients, 1349 met the inclusion criteria for the study (Figure 1).1349 patients with a mean age of 51.3 ± 18.1 years, who presented to health centers due to the persistent clinical symptoms after COVID-19 were included into the study.The majority of study participants were female (N = 837, 62.0%) and the most common chronic comorbidity in the studied cohort was hypertension, present in 34.2% of the analysed patients.In most patients, the course of the COVID 19 infection was mild or moderate; however 200 of the patients required hospitalization for acute phase COVID-19.
(p < 0.001) and mean arterial (p < 0.001) blood pressure values.Furthermore, this group of patients was significantly more likely to have an elevated SBP ≥ 130 mmHg (47.8% vs. 34.8%respectively, p = 0.023).A detailed summary of ABPM and 24 h ECG Holter monitoring findings is presented in Table 4.The studied groups did not differ significantly in the prevalence of ventricular and supraventricular arrythmias with the exception to atrial fibrillation (AF -1.5% vs. 0.1%, p = 0.003).However, due to the limited number of patients who experienced AF (one in the IST positive group and F I G U R E 1 Flowchart of study group.one in the IST negative group), this finding should be treated with caution.
From a medical point of view, in addition to the difficulties of managing patients in the acute phase of the disease, problems have arisen in the diagnosis and treatment of individuals with the post-COVID syndrome (PCS).This term refers to a broad spectrum of symptoms of unknown pathogenesis, including but not limited to T A B L E 2 Clinical characteristics of the whole study group and subgroups stratified by the presence of inappropriate sinus tachycardia.Variable Whole group (N = 1349) N (%)/M ± SD IST + (N = 69) N (%)/M ± SD IST − (N = 1280) N (%)/M ± SD

T A B L E 3
Summary of laboratory results of the whole study group and subgroups stratified by the presence of inappropriate sinus tachycardia.Variable Whole group (N = 1349) N (%)/M ± SD IST + (N = 69) N (%)/M ± SD IST − (N = 1280) N (%)/M ± SD p TG [mmol/L] 19Infection Severity Rating Scale.
− One of the following: hospitalization with pneumonia, respiratory failure, intensive care unit (ICU) treatment, respiratory support or thromboembolic complications during hospitalization/home isolation or for home isolation: symptoms persisting for more than 14 days, temperature above 38°C, dyspnea, oxygen saturation <94% persisting for at least 3 days, or a subjective patient assessment of '3′ on a scale of 0 to 3 points.
11sfunction, headache and osteoarticular pain.In addition, the presence of memory and concentration problems, difficulty speaking, inability to focus attention and reduced mental acuity, all defined as brain fog, were assessed.11Accordingto the WHO definition, the diagnosis of the long-term COVID was established based on of the presence of at least one symptom within 12 weeks p Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; IST, inappropriate sinus tachycardia; kg, kilograms, M, mean; N, number; SD, standard deviation.# Chi square.*Mann-Whitney U, the p values refer to comparisons between the group with (IST+) and without (IST−) a diagnosis of sinus tachycardia.
Univariate analysis of risk factors for the development of the inappropriate sinus tachycardia.Assessment of risk factors for the development of the inappropriate sinus tachycardia in a multivariate composite model with backward stepwise analysis.