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. 2023 Apr 21;247:103094. doi: 10.1016/j.autneu.2023.103094

Exaggerated blood pressure elevation in response to orthostatic challenge, a post-acute sequelae of SARS-CoV-2 infection (PASC) after hospitalization

J Antonio González-Hermosillo G a, Esteban Jorge Galarza b, Onasis Vicente Fermín a, José Manuel Núñez González a, Lucia Mariel Félix Álvarez Tostado a, Marco Antonio Estrada Lozano a, Claudia Ruíz Rabasa a, María del Rocio Martínez Alvarado b,⁎
PMCID: PMC10121145  PMID: 37137186

Abstract

Objective

Post-acute sequelae of SARS-COV-2 (PASC) are emerging as a major health challenge. Orthostatic intolerance secondary to autonomic failure has been found in PASC patients. This study investigated the effect of COVID-19 after recovery on blood pressure (BP) during the orthostatic challenge.

Research design and methods

Thirty-one out of 45 patients hospitalized due to COVID-19-related pneumonia that developed PASC and did not have hypertension at discharge were studied. They underwent a head-up tilt test (HUTT) at 10.8 ± 1.9 months from discharge. All met the PASC clinical criteria, and an alternative diagnosis did not explain the symptoms. This population was compared with 32 historical asymptomatic healthy controls.

Results

Exaggerated orthostatic blood pressure response (EOPR)/orthostatic hypertension (OHT) was detected in 8 out of 23 (34.7 %) patients, representing a significantly increased prevalence (7.67-fold increase p = 0.009) compared to 2 out of 32 (6.4 %) asymptomatic healthy controls matched by age, who underwent HUTT and were not infected with SARS-CoV-2.

Conclusions

This prospective evaluation in patients with PASC revealed abnormal blood pressure rise during the orthostatic challenge, suggesting of autonomic dysfunction in a third of the studied subjects. Our findings support the hypothesis that EOPR/OHT may be a phenotype of neurogenic hypertension. Hypertension in PASC patients may adversely affect the cardiovascular burden in the world.

Keywords: Pos acute sequelae of SARS-CoV2, Long-COVID-19, Orthostatic hypertension, Neurogenic hypertension

1. Introduction

Several weeks after recovering from COVID-19 infection, many patients report long-lasting symptoms. This chronic condition is still being studied and referred as post-COVID-19 syndrome, post-acute sequelae of SARS-COV-2 infection (PASC), long COVID, and long haul COVID. The etiologies of PASC are uncertain, with some linking it to an autoimmune condition or persistent low-grade brain inflammation after the resolution of acute COVID-19 (Al-Kuraishy et al., 2021).

Syndromes associated with orthostatic intolerance (OI) (defined as symptoms that worsen upon assuming the upright posture an improved by recumbency), including vasovagal syncope, orthostatic hypotension, postural tachycardia syndrome (POTS), and orthostatic intolerance not meeting criteria for POTS have been reported after COVID-19 (Blitshteyn and Whitelaw, 2021; Hira et al., 2022). In addition, a prospective evaluation in patients with PASC revealed OI on the head-up tilt test (HUTT) in nearly all subjects (Jamal et al., 2022).

In healthy individuals, the arterial baroreflex maintains blood pressure while standing. However, an exaggerated counterregulatory response in some people increases the blood pressure while standing.

Two phenotypes may expressed elevation of blood pressure during orthostasis: 1) exaggerated orthostatic pressor response (EOPR), defined as a systolic blood pressure increase while standing by at least 20 mmHg, 2) Orthostatic hypertension (OHT), an upright systolic blood pressure ≥ 140 mmHg as proposed by a consensus statement (Jordan et al., 2022).

In a recent study, new onset hypertension, defined as values ≥140/90 mmHg, was observed in 11.8 % of hospitalized patients with acute COVID-19 (Akpek, 2022). Chen found that 8.4 % of patients without prior hypertension had a rise in blood pressure after COVID-19 (Chen et al., 2021).

COVID-19 infection may cause increased sympathetic activity through emotional stress, hypoxia, immune/inflammatory factors, or renin-angiotensin system dysregulation and brain oxidative stress (Al-Kuraishy et al., 2021). Besides, the hyperadrenergic state may play a role in the hypertension observed in some patients with PASC.

This study aimed to explore the effect of PASC on blood pressure (BP) and its change during the orthostatic challenge.

2. Materials and methods

2.1. Study cohort

We enrolled consecutive adult patients hospitalized with moderate to severe confirmed COVID-19 pneumonia (World Health Organization, 2020). As shown in Fig. 1 , 225 patients were admitted to the intensive care unit of the National Institute of Cardiology Ignacio Chavez from April 11th, 2020, to September 15th, 2020, and 160 survivors were discharged by September 22nd 2020. All patients had confirmed COVID-19 RT-PCR positive test. We excluded the following patients: 1) Those that died before the follow-up started, 2) Those that declined to participate, and 3) Those unable to be contacted. The remaining 130 survivors were interviewed by phone with a previously designed questionnaire (Carruthers et al., 2003). Follow-up was continued for a mean of 10.8 ± 1.9 months, 45 patients met the definition of PASC, and their symptoms were not explained by an alternative diagnosis (normal ECG and echocardiogram). Fatigue, brain fog, memory problems, palpitations, headache, muscle/joint pain, dizziness, near syncope/syncope, and unrefreshing sleep suggesting possible autonomic dysfunction (mainly orthostatic intolerance) were present a minimum of 3 months after recovery from acute COVID-19 infection and these symptoms diminished over time (González-Hermosillo et al., 2021). An alternate etiology of symptoms after PASC diagnosis was discarded. Thirty-one patients were submitted to a passive HUTT. Eight patients with a previous history of arterial hypertension were excluded. Therefore, only 23 patients (51.5 ± 8.3 years old) were selected for the final evaluation and were compared with 32 healthy asymptomatic subjects matched by age, with negative HUTT (no orthostatic intolerance) from a sample of volunteer individuals without a history of COVID-19 infection (Jorge-Galarza et al., 2021). The study participants were categorized as follows: group 1, including both: patients with an exaggerated orthostatic pressor response and patients with orthostatic hypertension (EOPR/OHT+). Group 2: patients with neither, exaggerated orthostatic pressor response and orthostatic hypertension (EOPR/OHT-). This study was carried out according to the Helsinki declaration and was approved by the local ethics committee. All participants received oral information about the study before inclusion and gave written informed consent.

Fig. 1.

Fig. 1

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Flow chart of patient's selection. PASC: post-acute sequelae of SARS-CoV-2 infection. HUTT: head up tilt table; Exaggerated Orthostatic Pressor Response and/or patients with Orthostatic Hypertension (EOPR/OHT).

2.2. Head-up tilt test

All subjects underwent a 30 min passive HUTT, 10.8 ± 1.9 months from PASC symptom onset. None of these patients were under medication. After 30 min of supine resting, baseline measurements were assessed during the last 5 min. Thereafter, subjects were tilted at a 70° angle in an upright position for 25 min and then returned to a supine position for 5 min recovery. Beat-to-beat blood pressure (BP) with a periodical automatic crosschecked (in intervals of 5 min) oscillometer BP measurement in the contralateral arm was continuously recorded using finger arterial plethysmography (Task Force Monitor, CNSystems, Graz, Austria). Since continuous beat-to-beat blood pressure measurements may cause artifacts, an additional automatic measurement from the oscillometric brachial cuff was obtained when an abrupt change in the blood pressure was observed. The arm with the adjusted finger cuff was positioned such that the lower arm remained near the hydrostatic indifference point at any posture. Spectral analysis of heart and blood pressure variability was done automatically. The selected data were averaged in the following stages: (1) baseline: from the last 5 min of the supine rest before the tilt, (2) the first minute of tilting, (3) every 5 min after that until the end of tilting.

2.3. Statistical analysis

The analysis was performed with SPSS v 15 (IBM statistics, Armonk, NY). Normal distribution was determined by the Shapiro-Wilk test. Continuous variables were reported as mean ± SD or median, interquartile range (IQ) as appropriate, and categorical variables were reported as number (%). The frequency of EOPR/OHT during HUTT in PASC patients was compared to healthy controls using a Chi-squared test. Comparisons between groups and within the time frame were performed through analysis of variance for repeated measures, according to the group (EOPR/OHT+ vs. EOPR/OHT-). The odd ratio for the presence of EOPR/OHT was adjusted for obesity using logistic regression. The differences were considered statistically significant with a p-value <0.05.

3. Results

Out of 23 qualified patients, 8 (34 %) had abnormal blood pressure response to orthostasis. None had abnormal blood pressure at hospital discharge (Table 2). Five had EOPR and three OHT+ fulfilling the current definition.

Table 2.

Clinical and laboratory characteristics of study participants with PASC.

Variable EOPR/OHT (−)
 EOPR/OHT (+)
 p
n-15 n-8
Age (years) 49.7 ± 9.6 54.3 ± 12.9 0.43
Women (%) 7 (50) 5 (62.5) 0.61
BMI (kg/m2) 28.2 ± 3.0 30.6 ± 5.6 0.02
SBP at hospital admission (mmHg) 117 ± 20 119 ± 21 0.87
DBP at hospital admission (mmHg) 72.7 ± 6.9 76.7 ± 13.7 0.007
HR at hospital admission (beats x min) 102 ± 19 88 ± 13 0.18
SBP at hospital discharge (mmHg) 116.3 ± 10.7 115.8 ± 9.7 0.68
DBP at hospital discharge (mmHg) 72.2 ± 10.4 73.3 ± 9 0.69
HR at hospital discharge (beats / min) 76 ± 9 77 ± 6 0.21
Lymphocytes (%) at hospital admission 8.3(4.6–17.8) 18(9.3.-23.2) 0.11
CRP (nmol/L) at hospital admission 1009(310–1901) 1171(338–2692) 0.72
D- Dimer (μg/L,DDU) at hospital admission 0.63(0.23–2.27) 0.24(0.18–0.43) 0.11
Ferritin (nmol/L) at hospital admission 485(229–994) 553(204–914) 0.89
Fibrinogen (g/L) at hospital admission 5.6(4.7–6.1) 4.6(4.06–5.4) 0.29
Hs-cTnI (pg/mL) at hospital admission 7.6(3.2–30.12) 5.2(3.4–35.1) 0.73
NT-proBNP (pmol/L) at hospital admission 19.6(7.3–55.5) 32.7(8.9–83.9) 0.55
IL-6 (pg/mL) at hospital admission 16.2(4.5–109) 9.7(4.5–43.1) 0.33
VEGF (pg/ml) at hospital admission 85.3(39.1–291) 81.6(26.3–114) 0.50
Length of hospital stay in days 13.3 ± 9 17.8 ± 14.5 0.03
Mechanical ventilation (%) 6 (43) 2(25) 0.68
Days on mechanical ventilation 15.6 ± 9 17 ± 5 0.24
Diabetes Mellitus n (%) 2(14) 2(25) 0.53
Coronary Heart Disease (%) 0 1(12) 0.17



PACS symptoms
Fatigue unrelated to exercise (%) 9(64.3) 7(87.5) 0.24
Dyspnea (%) 5(35.7) 4(50) 0.51
Disturbance sleep (%) 6(43) 6(75) 0.14
Postural dizziness (%) 5(35.7) 5(62.5) 0.22
Chest pain (%) 3(21.4) 4(50) 0.16
Tachycardia unrelated to exercise (%) 6(43) 1(12.5) 0.14
Headache (%) 5(35.7) 6(75) 0.07
Muscle pain (%) 5(35.7) 7(87.5) 0.01
Joint pain (%) 5(35.7) 6(75) 0.07
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PASC: Post-acute sequelae of SARS-COV-2, Exaggerated Orthostatic Pressor Response and patients with Orthostatic Hypertension (EOPR/OHT). BMI: body mass index, SDP: systolic blood pressure, DBP: diastolic blood pressure, HR: heart rate, CRP: C - reactive protein, Hs-cTnI: High sensitive cardiac Troponin I, IL-6: Interleukin-6, VEGF: Vascular Endothelial Growth Factor. Data are presented as mean (SD), median (Interquartile range) and n (%); p values were calculated by t-student, Mann-Whitney U test or Chi-square.

Compared to historical healthy control subjects without COVID-19 submitted to HUTT, patients with PASC had a higher prevalence of obesity (p = 0.04) and EOPR/OHT+ (p = 0.009), Table 1 . The PASC patients had a 7.67-fold increased risk of presenting EOPR/OHT+ compared to subjects not infected with SARS-CoV-2. After adjustment for obesity, this risk decreased to 6.55 (CI: 1.18–36.08, p =0.03).

Table 1.

Clinical characteristics of Post-Acute Sequelae of SARS-CoV-2 infection patient's vs healthy controls.

Variable Healthy Controls
 PASC
 p
(n = 32) (n = 23)
Age (years) 47.7 ± 10.7 51.1 ± 10.7 0.252
Body mass index (kg/m2) 26.3 ± 3.20 29.2 ± 4.1 0.006
Women, n (%) 16 (50) 14 (60) 0.425
Obesity, n (%) 5 (15.6) 9 (39.1) 0.048
Supine systolic blood pressure (mmHg) 113 ± 13 109 ± 12 0.279
Supine diastolic blood pressure (mmHg) 75.1 ± 13 72.6 ± 8.5 0.412
Supine heart rate (beats/min) 66 (61–74) 64 (60–74) 0.969
Exaggerated orthostatic pressor response/orthostatic hypertension, n (%) 2 (6.3) 8 (34.8) 0.009
Odds ratio for orthostatic hypertension, (95 % C.I.) 1 (reference) 7.67 (1.56–58.7) 0.015
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PASC: Post-acute sequelae of SARS-COV-2.

Data are expressed as mean ± standard deviation, median (interquartile range), number of subjects (%), Odds ratio (95 % confidence interval C.I.).

PASC patients with EOPR/OHT+ were older, had a higher body mass index and diastolic BP (dBP) at hospital admission, and had a more extended hospital stay than EOPR/OHT- patients. The symptoms were similar in both groups (Table 2 ). At the supine position, systolic (sBP), diastolic (dBP) and mean BP (mBP) were similar in the EOPR/OHT+ group compared to the EOPR/OHT- group. On tilting, sBP, dBP and mBP increased in both groups, but the rise was significantly higher in sBP and mBP at 5, 10, 15 and 20 min of tilting in EOPR/OHT+ patients. The EOPR/OHT+ patients had significantly higher dBP at 10 and 20 min of tilting compared to the other group. Maximum sBP was increased during HUTT compared with supine values in both groups, but only in EOPR/OHT+ group the rise reached statistical significance (p = 0.007), Fig. 2 . Compared with EOPR/OHT-, EOPR/OHT+ did not show significant heart rate differences throughout the study (Supplementary table 1). Frequency domain spectral measures of heart rate and blood pressure variability were not different between groups (supplementary tables 2–3). During HUTT, no difference was found in the frequency of orthostatic symptoms between the groups (supplementary table 4). Of note, no patients had a heart rate increase suggestive of POTS, vasovagal syncope, or orthostatic hypotension during tilt.

Fig. 2.

Fig. 2

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Blood pressure values throughout the HUTT in PACS patients with exaggerated orthostatic pressor response and patients with orthostatic hypertension (EOPR/OHT+) and PACS patients without exaggerated orthostatic pressor response and patients without orthostatic hypertension (EOPR/OHT-). A) Systolic blood pressure, B) Diastolic blood pressure. C) Mean blood pressure. D) Maximum systolic blood pressure reached during HUTT. PACS: post-acute sequelae of SARS CoV2 infection, HUTT: head-up tilt test. S: supine condition. Up y down *: p < 0.05.

4. Discussion

The main findings of the current study were: 1) A subset of long-term symptomatic patients with confirmed COVID-19, after they recovered, had increased blood pressure unmasked by orthostatic challenge, suggesting a high sympathetic tone. 2) This new onset exaggerated orthostatic pressor response/ orthostatic hypertension was detected in 8/23 patients, a significant increase in frequency compared to 2/32 healthy subjects who were not infected with SARS-CoV-2. 3) No heart rate increase during orthostatic challenge suggested POTS in any of the subjects studied. 4) Overweight and obesity rates were higher in patients with PASC and those with EOPR/OHT+ compared with non-infected normotensive healthy controls and PASC patients without EOPR/OHT.

Reports of COVID-19-related autonomic dysfunction have been limited. The most common autonomic manifestation reported is orthostatic intolerance, not meeting the criteria for POTS. None of our patients had POTS nor initial orthostatic hypotension, which are considered common cardiovascular autonomic abnormalities in PASC (Hira et al., 2022). Orthostatic intolerance symptoms not meeting criteria for POTS were similar in patients from both groups during HUTT. This former phenotype may have been present earlier after acute infection and disappeared before testing.

Few reports have detected hypertension as sequelae of COVID-19. Akpek (2022) found 12 % and Zeng (Zeng et al., 2021) 19.3 % of patients with new-onset hypertension after recovery. In the last study, the hypertensive compared with normotensive patients were older, a similar finding to ours.

Goodman reported six non-hospitalized patients with persistent symptoms of orthostatic intolerance after COVID-19 who underwent HUTT (Goodman et al., 2021). Postural tachycardia was seen in four patients, including two patients with hypertension and only one with isolated postural hypertension. The time from symptom onset to the evaluation in this study was under three months compared to 10.8 ± 1.9 months in our research. The longer time to assess in our study and the severity of COVID-19 may explain the higher prevalence of EOPR/OHT+.

Patients following a viral infection can develop “a post-viral syndrome” that is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex illness that has been linked to COVID-19 sharing angiotensin II (Ang II) upregulation, premature endothelial senescence, intestinal barrier dysfunction, and microbial translocation from the gastrointestinal tract into the systemic circulation. These hypotheses have been validated, and viral infection-induced endothelial cellular senescence and microbial translocation were documented in acute SARS-CoV-2 infection, PASC, and ME/CFS (Sfera et al., 2022). Campen et al. (2021) compared orthostatic symptoms in daily life and during HUTT, HR and BP response to tilt in long COVID-19 patients, ME/CFS controls, and healthy controls. There were no significant differences in ME/CFS symptom prevalence as well the HR and BP response between the long COVID-19 patients and the ME/CFS patients. All long COVID-19 patients developed POTS during tilt and no hypertension. As compared to our study, their sample was smaller, younger (30 years old), with less severe disease, and duration of symptoms.

Orthostatic intolerance in PASC is not always associated with POTS. Monaghan et al. (2022) investigated predictors of OI in adults reporting long COVID symptoms. In that study, OI during active stand was reported in 66 %, and POTS was infrequent (2 %), with a median delay to testing of 302 days. Interestingly, they found evidence of diastolic hypertension in this cohort.

Our investigation differs from the one by Jamal (Jamal et al., 2022) in patients with PASC using HUTT; they did not find any patient with EOPR/OHT. The methodology could explain the difference since they performed fixed interval BP monitoring instead of beat-to-beat measurements during orthostatic challenge to detect hypertension. Another difference was the long period from onset of PASC symptoms to HUTT, 5.1 ± 3.0 months vs. 10.8 ± 1.9 months in our study.

The presence of EOPR/OHT+ in our series and sustained hypertension in the previously mentioned case reports and cohort studies where BP was significantly higher in the post-COVID-19 period than upon admission (Chen et al., 2021), is suggestive of a persistent hyperadrenergic state in some patients after COVID-19. Few studies have addressed the autonomic imbalance to try to explain the mechanisms of hypertension in patients with SARS-CoV-2 infection and PASC. SARS-CoV-2 also spreads to the brain (Wu et al., 2020). The renin-angiotensin system's role in hypertension in COVID-19 has been recently reviewed (Chen H et al., 2023). Dysregulation of the renin-angiotensin system (RAS) is one of the clinical implications of SARS-CoV-2 infection. The binding of SARS-CoV-2 spike proteins to angiotensin-converting enzyme 2 (ACE2) facilitates the virus entry into host cells. ACE2 also regulates the brain RAS, critical in regulating blood pressure. ACE2 catalyzes the conversion of angiotensin I to angiotensin-(1–9) and Ang II to angiotensin (1–7) (Wang et al., 2020). An ACE2/ACE ratio imbalance can occur in COVID-19 patients due to reduced activity of ACE2 or increased activity of ACE with excessive production of Ang II. Since over-expressed Ang II in the brain during COVID infection has pro-oxidative and pro-inflammatory actions, elevated Ang II promotes endothelial dysfunction, inflammation, vascular complications and increased central sympathetic activity. This chronic low-level inflammation and the increased sympathetic activity results in changes in the arterial wall, such as vascular remodeling, that may contribute to hypertension in PASC (Muhamad et al., 2021). Therefore, it is possibly that the consequences of the RAS system dysregulation initiated during the acute stage of the infection may persist even though the virus spike protein is no longer present. Further studies are required to explore this hypothesis. It has been shown that brain RAS overactivity could induce hypertension (Kulkarni et al., 2022). Sympatho-excitation has also been shown to be associated with the development of hypertension (Kishi, 2013). The rostro-ventro-lateral medulla (RVLM), the vasomotor center, is essential in regulating the sympathetic nervous system by determining basal central sympathetic outflow. It has been observed that neuroinflammation and oxidative stress in the RVLM, enhancing sympathetic outflow to blood vessels, are involved in the development of neurogenic hypertension in different experimental hypertensive models (Koga et al., 2008; Wu et al., 2012).

Since the demonstration that the sympathetic nervous system exerts a fundamental role in the homeostatic control of blood pressure, the hypothesis has been advanced that abnormalities in the adrenergic regulation of either cardiac output or peripheral vascular resistance might represent the pathophysiological hallmarks of neurogenic hypertension. It has long been known that abnormal autonomic function, particularly sympathetic hyperactivity, has a role in the origin, progression and outcome of hypertension, with renewed interest in recent years. Neurogenic hypertension can be defined as hypertension in patients whose sympathetic nervous system plays a significant or even dominant role as a driving force (Mann, 2018). The factors that cause central sympathetic overactivity in human neurogenic hypertension are poorly understood and remain hypotheses.

Pathophysiological studies on orthostatic hypertension are scarce. An orthostatic pressor response or orthostatic hypertension could occur when neurohumoral adjustments to standing overshoot (Jordan et al., 2020). EOPR/OHT could be a distinct phenotype of neurogenic hypertension. Orthostatic hypertension, which appears to be mediated through excess adrenergic activation while standing, is a blood pressure trait among patients with and without arterial hypertension, both in younger and older persons. Most conditions associated with OHT are associated with altered cardiovascular adrenergic control mechanisms (Petersen et al., 2021). Compared with control persons, patients with POTS, characterized by increased cardiac sympathetic activation, are more likely to exhibit a pressor response to standing (Shibao et al., 2005). An orthostatic increase in BP may herald overt hypertension later in life (Rose et al., 2002). Dorogovtsev et al. (2022) showed the feasibility of detecting preclinical hypertension using the HUTT.

Few studies have addressed the heart and blood pressure variability to try to explain cardiac autonomic activity in patients with PASC. The results are conflicting since measurement methods, population, and the severity and stage of infection at which testing was performed, all differed between studies (Kaliyaperumal et al., 2021; Stábile da Silva et al., 2023). We did not find significant differences in heart and blood pressure variability spectral indices in this study (Supplementary tables).

4.1. Limitations

Some limitations of this study were the small sample size, the enrollment at a single center and that only moderate to severe hospitalized COVID-19 patients with pneumonia were included, so the results may only apply to some of the post-COVID population. Only 31 patients were investigated out of 160 COVID-19 survivors, which is an important limitation. Unfortunately, we did not compare the PASC patients with a matched asymptomatic control group of COVID-19 survivors due to refusal to be studied. Neither; patients with orthostatic intolerance without COVID-19 were studied. Another important limitation of our study was that the diagnosis of arterial hypertension was not confirmed by 24-hours ambulatory blood pressure monitoring, which is recommended by the current hypertension guidelines.

Although the frequency of EOPR/OHT was higher in PASC patients compared to healthy asymptomatic historical controls in our study, we cannot be sure that the findings suggest new-onset hypertension in these individuals, even though they were not found hypertensive at discharge.

5. Conclusions

Based on the data presented, EOPR/OHT during tilt testing should be investigated in hospitalized COVID-19 convalescents of moderate to severe acute infection who developed PACS presenting with unexplained orthostatic intolerance. Therefore, physicians ought to know of the potential risk for new-onset hypertension during the post-COVID-19 era.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Informed consent statement

Informed consent was obtained from all subjects involved in the study.

CRediT authorship contribution statement

J. Antonio González-Hermosillo G: Conceptualization, Writing – original draft, Writing – review & editing, Resources, Supervision. Esteban Jorge Galarza: Formal analysis, Investigation, Writing – review & editing. Onasis Vicente Fermín: Methodology, Data curation, Writing – review & editing. José Manuel Núñez González: Methodology, Data curation, Writing – review & editing. Lucia Mariel Félix Álvarez Tostado: Data curation, Writing – review & editing. Marco Antonio Estrada Lozano: Data curation, Writing – review & editing. Claudia Ruíz Rabasa: Resources. María del Rocio Martinez Alvarado: Formal analysis, Investigation, Writing – review & editing, Supervision.

Declaration of competing interest

The authors declare that they have no conflict of interest and there are no competing interest concerning the content of this paper.

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.autneu.2023.103094.

Appendix A. Supplementary data

Supplementary tables

mmc1.docx (40.6KB, docx)

Data availability

No data was used for the research described in the article.

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