Impact of breakthrough COVID-19 cases during the omicron wave on vascular health and cardiac autonomic function in young adults.

We and others have previously shown that COVID-19 results in vascular and autonomic impairments in young adults. However, the newest variant of COVID-19 (Omicron) appears to have less severe complications. Therefore, we investigated whether recent breakthrough infection with COVID-19 during the Omicron wave impacts cardiovascular health in young adults. We hypothesized that measures of vascular health and indices of cardiac autonomic function would be impaired in those who had the Omicron variant of COVID-19 when compared with controls who never had COVID-19. We studied 23 vaccinated adults who had COVID-19 after December 25, 2021 (Omicron; age, 23 ± 3 yr; 14 females) within 6 wk of diagnosis compared with 13 vaccinated adults who never had COVID-19 (age, 26 ± 4 yr; 7 females). Macro- and microvascular function were assessed using flow-mediated dilation (FMD) and reactive hyperemia, respectively. Arterial stiffness was determined as carotid-femoral pulse wave velocity (cfPWV) and augmentation index (AIx). Heart rate (HR) variability and cardiac baroreflex sensitivity (BRS) were assessed as indices of cardiac autonomic function. FMD was not different between control (5.9 ± 2.8%) and Omicron (6.1 ± 2.3%; P = 0.544). Similarly, reactive hyperemia (P = 0.884) and arterial stiffness were not different between groups (e.g., cfPWV; control, 5.9 ± 0.6 m/s and Omicron, 5.7 ± 0.8 m/s; P = 0.367). Finally, measures of HR variability and cardiac BRS were not different between groups (all, P > 0.05). Collectively, these data suggest preserved vascular health and cardiac autonomic function in young, otherwise healthy adults who had breakthrough cases of COVID-19 during the Omicron wave.NEW & NOTEWORTHY We show for the first time that breakthrough cases of COVID-19 during the Omicron wave does not impact vascular health and cardiac autonomic function in young adults. These are promising results considering earlier research showing impaired vascular and autonomic function following previous variants of COVID-19. Collectively, these data demonstrate that the recent Omicron variant is not detrimental to cardiovascular health in young, otherwise healthy, vaccinated adults.

INTRODUCTION

The COVID-19 pandemic has affected nearly 80 million Americans to date, many of whom are young adults without preexisting conditions (1). Although initially thought to be a respiratory disease, it is increasingly recognized that COVID-19 induces vascular dysfunction in persons who become infected (2). Indeed, we and others have previously shown that COVID-19 resulted in reduced endothelial function indicated by decreased flow-mediated dilation (FMD) (3–5), impaired microvascular reactivity (i.e., blunted reactive hyperemia) (3, 4), and increased arterial stiffness (3, 6). Furthermore, persons with COVID-19 were also shown to have potential impairments in cardiovascular autonomic function with elevated muscle sympathetic nervous system activity (7) and reduced blood flow responses to exercise (8). Collectively, these findings suggest that COVID-19 negatively influences the cardiovascular and autonomic nervous system in young, otherwise healthy adults, which may result in increased cardiovascular disease risk in this population (9).

Importantly, since these original reports, a new, less virulent but much more transmissible variant of SARS-CoV-2 has emerged (i.e., Omicron; B.1.1.529). Likewise, vaccination rates against COVID-19 have increased significantly in the past year, with 64.7% of persons in the United States being vaccinated as of March 21, 2022 (10). However, because the Omicron variant is highly contagious, even the infection rates among the vaccinated (i.e., breakthrough cases) are high (11, 12). Therefore, in the present study, we aimed to characterize whether recent breakthrough illness with COVID-19 during the Omicron wave impacted vascular and cardiac autonomic function in vaccinated young adults. We hypothesized that measures of vascular health (e.g., FMD, arterial stiffness) and indices of cardiac autonomic function [e.g., heart rate (HR) variability and cardiac baroreflex sensitivity (BRS)] would be reduced when compared with age, sex, body mass index (BMI), and ethnicity-matched, vaccinated controls who never had COVID-19.

METHODS

Twenty-three adults who had COVID-19 (Omicron, 14 females) were recruited from The University of Texas at Arlington (UTA) community and through word of mouth between January 14 and February 28, 2022, and compared with 13 healthy controls (7 females) who never had COVID-19 (self-report). Data from five of the controls have been previously reported (4). All participants were nonsmokers, were not on any prescription medication, and were free from cardiovascular, metabolic, or neural disease per a medical health history questionnaire. Written, informed consent was obtained after a verbal explanation of all laboratory measurements and protocols. On the experimental day, all participants arrived in the morning following an overnight fast having also abstained from caffeine for 12 h, and alcohol and strenuous exercise for at least 24 h. Pregnancy tests were performed on all female participants. All experimental procedures conformed to the Declaration of Helsinki and were approved by the UTA Institutional Review Board (2021-0197).

All participants were vaccinated against COVID-19 (i.e., had completed their final dose of an approved vaccine at least 14 days before assessment). Eleven participants had received their booster dose. For the Omicron group, the number of weeks from the time of their most recent vaccine dose to COVID-19 diagnosis ranged from 2 to 45 wk (mean, 25 ± 13 wk). All Omicron participants were diagnosed by RT-PCR or rapid antigen test as of December 25, 2021, or later. The average number of days past diagnosis at the time of testing was 30 ± 9 (range: 16–42). The average number of days from symptom onset to diagnosis was 3 ± 2 (range: 0–8). None of the Omicron participants required hospitalization for their infection and rated their illness as mild to moderate in severity at their diagnosis/onset of symptoms. Primary symptoms at diagnosis included fever, chills, cough, sore throat, fatigue, congestion, and headache. Participants were screened before their study visit, and none had any persistent fever, cough, sore throat, or difficulty breathing at the time of testing. Four participants reported symptoms at the time of testing including fatigue (n = 2), back pain (n = 1), and loss of taste (n = 1), which they rated as a 3 ± 1 (out of 10) in terms of severity.

On arrival at the laboratory, height and weight were measured on a stadiometer and BMI was calculated as kg/m2. Brachial artery FMD and reactive hyperemia were used as measures of macro- and microvascular function, respectively, and determined using current guidelines as previously described (4, 13). Briefly, following at least 20 min of supine rest, we measured brachial artery diameter and blood velocity using duplex Doppler ultrasound (GE Logiq P5, Milwaukee, WI) during 5 min of quiet rest, 5 min of cuff inflation (rapidly inflating cuff set to 220 mmHg; Hokanson, Bellevue, WA), and 3 min of postocclusion recovery. Brachial artery diameter and weighted mean blood velocity were determined continuously during 2 min of baseline and during 30 s before cuff release through to the end of recovery using customized wall tracking and edge detection software (LabView, National Instruments, Austin, TX). FMD was calculated as the three-beat average peak change in absolute (mm) and relative (%) diameter compared with baseline diameter. We calculated the shear rate as 8 × mean blood velocity/diameter and the shear stimulus for FMD as the hyperemic shear rate area under the curve (AUC) to peak brachial artery dilatation as previously reported (4). Reactive hyperemia was determined as the three-beat average of the peak brachial artery blood velocity following cuff release. We were unable to obtain high-quality images in two Omicron participants because of technical issues; therefore, FMD data represent 13 control and 21 Omicron individuals.

After a minimum of 5 min following the end of FMD recovery, carotid-to-femoral pulse wave velocity (cfPWV) was determined using simultaneous carotid tonometry and femoral cuff occlusion (SphygmoCor XCEL 1.3, Atcor Medical, Sydney, Australia) as previously described (4). cfPWV was calculated as the carotid-femoral artery distance divided by the pulse transit time. We were unable to obtain a measure of cfPWV in one Omicron participant. Aortic blood pressure (BP) and augmentation index (AIx, %) were determined using brachial artery cuff inflation (SphygmoCor XCEL 1.3), and AIx corrected for an HR of 75 beats/min was recorded. For cfPWV, AIx, and aortic BP measures, an average of at least two consistent measurements were used for each participant according to guideline recommendations (14).

We next instrumented participants to measure HR using an electrocardiogram (lead 2; model Q710, Quinton, Bothell, WA), and a pneumobelt was placed around the abdomen (Pneumotrace II 1132, UFI, Morro Bay, CA) to monitor for respiratory excursions. We measured beat-by-beat arterial BP on the left finger (Finometer PRO, Finapres Medical Systems, Amsterdam, The Netherlands) and automated brachial BP on the right arm (Welch-Allyn, Skaneateles Falls, NY). After 10 min of quiet rest, HR and BP were recorded continuously during a 5-min resting period with stable breathing. Resting systolic and diastolic BP (SBP and DBP, respectively) were determined as the average of four BP measurements. We calculated beat-to-beat BP variability from Finometer measures as the standard deviation (SD) and average real variability (ARV) of each SBP, DBP, and mean arterial pressure (MAP). ARV was determined as the average absolute difference in BP between consecutive heartbeats (15, 16).

HR variability was determined in the time domain (root mean squared of successive difference in the R-R interval; RMSSD) and frequency domain [high-frequency (HF; 0.15–0.40 Hz) and low-frequency (LF; 0.04–0.15 Hz) power] using the R-R interval (RRI) (17). Autonomic balance was interpreted as the LF-to-HF ratio. Cardiac BRS was determined using the sequence method (Nevrokard software, Izola, Slovenia) as previously described (18). Briefly, sequences where both BP and RRI are rising over at least three consecutive cardiac cycles were used to determine up gains and vice versa for down gains. Overall gains were determined as all sequences combined.

A venous blood sample was collected for the measurement of high-sensitivity C-reactive protein (hsCRP) as a marker of inflammation. Blood samples were processed by a local laboratory (LabCorp) using an immunochemiluminometric assay. Finally, participants filled in the long form of the International Physical Activity Questionnaire (IPAQ) assessing their physical activity levels during the past 7 days (19).

Statistical Analysis

All data are presented as means ± SD. Data analysis and graphical representation were completed using GraphPad Prism (v9.3.1) except for FMD (%) corrected for shear stress using an analysis of covariance (ANCOVA) in SPSS (IBM, v25). Two-tailed unpaired t test was used to determine differences between control and Omicron groups for all normally distributed data. Data that were not normally distributed according to the Shapiro–Wilks test were compared using the Mann–Whitney U test. Significance differences between groups were determined as P < 0.05.

RESULTS

Participant Characteristics

Control and Omicron groups were well matched for general characteristics and race/ethnicity (Table 1). Self-reported physical activity levels from the IPAQ were also not different between groups (control, 3,220 ± 3,025; Omicron, 4,502 ± 5,984 MET min/wk; P = 0.477). Resting hemodynamics are presented in Table 2 and were not different between groups for resting HR, brachial BP, and central aortic BP. Finally, hsCRP was not different between the control (1.65 ± 2.39 mg/L) and Omicron (1.41 ± 1.55 mg/L; P = 0.736) groups.

Table 1.

Participant demographics

	Control	Omicron	P Value
n	13	23
Anthropometrics
Age, yr	26 ± 4	23 ± 3	0.098
Sex, males/females	6/7	9/14	0.681
Height, cm	169.5 ± 7.7	167.6 ± 10.6	0.588
Weight, kg	73.7 ± 11.1	71.7 ± 17.5	0.718
Body mass index, kg/m2	25.7 ± 4.1	25.3 ± 4.8	0.811
Race and ethnicity
Hispanic/Latino	2 (15)	4 (17)	0.877
Non-Hispanic/Latino	11 (85)	19 (83)
White	6 (46)	13 (56)	0.533
Asian	5 (38)	8 (35)
Black/African American	1 (8)	3 (13)
Other/multiracial	1 (8)	0 (0)

Dichotomous values are means ± SD (n, number of participants), compared using a two-tailed unpaired t test. Categorical values are n (%), compared using the χ2 test. P < 0.05 was used to determine significant differences between groups.

Table 2.

Resting cardiovascular measures and cardiac baroreflex sensitivity

	Control	Omicron	P Value
n	13	23
Resting cardiovascular measures
Heart rate, beats/min	59 ± 7	61 ± 9	0.164
Brachial SBP, mmHg	113 ± 7	109 ± 6	0.088
Brachial DBP, mmHg	69 ± 6	67 ± 5	0.214
Brachial MAP, mmHg	84 ± 6	82 ± 5	0.136
Aortic SBP, mmHg	104 ± 8	102 ± 7	0.401
Aortic DBP, mmHg	72 ± 7	71 ± 5	0.549
Aortic MAP, mmHg	83 ± 7	82 ± 5	0.614
Cardiac baroreflex sensitivity
Overall gain, ms/mmHg	21.1 ± 8.6	23.3 ± 13.1	0.948
Up gain, ms/mmHg	24.1 ± 17.4	24.3 ± 14.3	0.721
Down gain, ms/mmHg	21.0 ± 8.2	22.4 ± 12.8	0.974

Values are means ± SD; n, number of participants. Resting cardiovascular measures were compared using a two-tailed unpaired t test. Cardiac baroreflex data were compared using a Mann–Whitney U test. P < 0.05 was used to determine significant differences between groups. DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure.

Peripheral Vascular Function and Arterial Stiffness

There were no differences between control and Omicron for resting brachial artery diameter (0.34 ± 0.06 and 0.32 ± 0.04 cm, respectively; P = 0.136) or resting brachial artery blood velocity (7.2 ± 3.0 and 9.1 ± 3.9 cm/s, respectively; P = 0.132). FMD measures reported as relative change (%) in diameter (Fig. 1) were not different between the control and Omicron groups. Similarly, there were no group differences in the absolute change in brachial artery diameter during FMD (control, 0.02 ± 0.01 cm; Omicron, 0.02 ± 0.01 cm; P = 0.818) or when corrected for shear stress AUC (P = 0.699). Time to peak diameter (control, 43 ± 7 s; Omicron, 43 ± 8 s; P = 0.978) and peak blood velocity following cuff release (Fig. 1) were also not different between groups. Findings for reactive hyperemia were similar when assessed as hyperemic velocity AUC to 30, 60, 90, or 120 s (P > 0.05 for all; for example, hyperemic velocity AUC to 120 s: control, 1,826 ± 654; Omicron, 1,754 ± 491; P = 0.717). We also found no difference in the time back to baseline brachial artery blood velocity (control, 151 ± 29 s; Omicron, 140 ± 37 s; P = 0.355). Central arterial stiffness (cfPWV; Fig. 1), AIx uncorrected for HR (control, 9.3 ± 9.3%; Omicron, 10.1 ± 10.0%; P = 0.814), and AIx corrected for a HR of 75 beats/min (Fig. 1) were also not different between groups.

Figure 1.

Macro- and microvascular function and arterial stiffness in individuals who never had COVID-19 (control, n = 13; 7 females) and those who had COVID-19 during the Omicron wave (Omicron, n = 23*, 14 females). Males are indicated by black symbols and females by white symbols. A–D: brachial artery flow-mediated dilation (FMD, %; A), reactive hyperemia (peak blood velocity following cuff release, cm/s; B), carotid-femoral pulse wave velocity (cfPWV, m/s; C), and augmentation index (AIx, %; D) corrected for a heart rate of 75 beats/min. Comparisons between groups were made using two-tailed, unpaired t test, and P < 0.05 was used to determine significant differences between groups. *In the Omicron group, n = 21 for FMD and reactive hyperemia and n = 22 for cfPWV. cfPWV, carotid-femoral pulse wave velocity.

Indices of Cardiac Autonomic Function

There were no differences between control and Omicron groups for BP variability when quantified as SD or ARV for SBP (Fig. 2, and , respectively), DBP, or MAP (P > 0.05 for all). HR variability measured in normalized units (NU) was not different between groups (Fig. 2, ). Similar results were found between control and Omicron groups when evaluating HR variability using absolute units of HF power (2,046 ± 2,140 ms2 vs. 3,542 ± 5,219 ms2, respectively; P = 0.360) and LF power (1,015 ± 1,126 ms2 vs. 1,692 ± 2,483 ms2, respectively; P = 0.360). Finally, there were no differences in cardiac BRS (Table 2) between the groups.

Figure 2.

Blood pressure variability and heart rate variability in individuals who never had COVID-19 (control; n = 13, 7 females) and those who had COVID-19 during the Omicron wave (Omicron, n = 23, 14 females). Males are indicated by black symbols and females by white symbols. A–F: systolic blood pressure (SBP) standard deviation (SD, mmHg; A), SBP average real variability (ARV, mmHg; B), root mean square of successive differences between normal heartbeats (RMSSD, RRI; C), low-frequency (LF) power [normalized units (NU), D], high-frequency (HF) power (NU; E), and LF-to-HF ratio (F). Comparisons between groups were made using two-tailed, unpaired t test, and P < 0.05 was used to determine significant differences between groups.

DISCUSSION

To our knowledge, this study was the first to investigate the effects of the Omicron variant of COVID-19 on vascular health and cardiac autonomic function in young adults. Contrary to our hypothesis, macro- and microvascular function, arterial stiffness, and indices of cardiac autonomic function were all similar between those who had contracted COVID-19 during the Omicron wave compared with those who never had COVID-19. Thus, these data show that breakthrough infection during the Omicron wave of COVID-19 did not result in vascular dysfunction or impairments in indices of cardiac autonomic function in otherwise healthy young adults who are vaccinated.

Studies have clearly demonstrated a negative effect of previous variants of COVID-19 on vascular function in young, otherwise healthy adults (3, 4, 6–8). Specifically, these studies showed that individuals who were in the acute phase of their illness (i.e., within 4 wk) demonstrated vascular dysfunction (3, 5), whereas those who were further away from infection only experienced lower FMD and reactive hyperemia if they had persistent symptoms (4). Similarly, arterial stiffness was elevated early on following COVID-19, but no effect was found after the acute phase (>4 wk) regardless of symptomology. Combined, the previous research demonstrated a potential transient effect of COVID-19, whereby the vascular dysfunction likely resolves in young, otherwise healthy, adults without persistent symptoms. Importantly, we studied all our participants in the Omicron group within 6 wk of infection and thus are confident that we would have detected a difference if one did exist. Together, our findings highlight the potential for differential vascular outcomes dependent on the COVID-19 variants and suggest that not all variants may be detrimental to cardiovascular health in young, otherwise healthy adults. This is all very promising; however, there is some recent evidence that cardiovascular health may still be impacted in the long term, even in those who were not hospitalized from COVID-19 (9). Therefore, follow-up studies will be needed to determine long-term cardiovascular health outcomes in persons who have been exposed to the different variants of COVID-19.

In the present study, we aimed to comprehensively assess cardiovascular health by also measuring resting BP (brachial and central) and BP variability. Previous reports have shown discrepancies in the effects of COVID-19 on resting BP in young adults in the laboratory setting, where some report increase in BP (6), whereas others report no difference (4, 7, 8). In contrast with the one study that showed increased central aortic BP following COVID-19 (6), we did not show a difference between groups. We also added an assessment of short-term beat-to-beat BP variability as a measure of cardiovascular health. This is important because higher BP variability may contribute to an increase in cardiovascular disease risk (20, 21). However, we showed no difference between Omicron and control groups, which compliments the rest of our findings. Limited evidence also suggests that COVID-19 may impact the autonomic nervous system in young, otherwise healthy adults (7), which represents a critical regulator of BP and cardiovascular health. One report showed increased muscle sympathetic nerve activity in individuals within 8 wk of diagnosis with COVID-19; however, we (22) and others (7) have shown no negative impact of COVID-19 on HR variability. This is in line with our current findings demonstrating no effect of Omicron on measures of cardiac autonomic function (i.e., HR variability and cardiac BRS). Together, these data are encouraging in that there appear to be minimal effects on cardiac autonomic function in young, vaccinated adults following COVID-19.

One consideration in the present study is that all the individuals were vaccinated; thus, we cannot extend our research findings to those who may have developed COVID-19 during this timeframe and were unvaccinated. However, many individuals who contracted the Omicron variant of COVID-19 in late 2021/early 2022 were vaccinated (23); thus this population represents an important group to study. Although we did not assess the variant of infection directly, we are confident that the individuals we studied were those who had the Omicron variant. This is due to evidence that the Omicron variant accounted for more than 90% of COVID-19 cases in Texas after mid-December 2021 and 98% of cases by January 4, 2022 (11); all of our participants were diagnosed between December 25, 2021 and January 24, 2022. According to the CDC, the types of symptoms are not reported to be much different with Omicron compared with previous variants; however, the severity of the disease is lesser (24). Notably, in the present study, fewer participants experienced persistent symptoms at their assessment compared with our previous work, which may have resulted from their vaccination status, but this requires further investigation. Overall, the lack of difference observed for cardiovascular health and cardiac autonomic function following Omicron is perhaps due to the combined effects of less severe infection, lack of persistent symptoms, and vaccination. However, it is important to note that our findings cannot be extended to older adults, or those with preexisting comorbidities, who may be at a greater risk for cardiovascular complications following COVID-19 (25). Future work will need to address the combined impact of both variant and vaccination (compared with none) on vascular function in those who develop COVID-19.

In conclusion, we show that young, otherwise healthy adults who had breakthrough infections during the Omicron wave of COVID-19 do not exhibit impairments in indices of cardiovascular health (macro- and microvascular function, arterial stiffness, resting BP, BP variability, HR variability, and cardiac BRS) when studied within 6 wk of diagnosis. Given previous findings showing vascular dysfunction within the same time frame following infection with earlier variants of COVID-19, these findings suggest that there are differential impacts of COVID-19 variants on vascular and autonomic health in young, otherwise healthy adults. This finding is likely attributable to the combination of less severity of the Omicron variant and vaccination status in these individuals. Considered collectively, these findings are promising given the large numbers of young adults who contracted the Omicron variant in late 2021/early 2022.

GRANTS

This work was supported by The University of Texas at Arlington College of Nursing and Health Innovation and American Heart Association Predoctoral Fellowship Grants 827597 (to D.N.) and 20PRE34990010 (to B.Y.S.).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

R.J.S., D.N., and P.J.F. conceived and designed research; R.J.S., D.N., A.-K.G., B.Y.S., and A.N.W. performed experiments; R.J.S., D.N., B.Y.S., and A.N.W. analyzed data; R.J.S., D.N., A.-K.G., and P.J.F. interpreted results of experiments; R.J.S. prepared figures; R.J.S. drafted manuscript; R.J.S., D.N., A.-K.G., B.Y.S., A.N.W., and P.J.F. edited and revised manuscript; R.J.S., D.N., A.-K.G., B.Y.S., A.N.W., and P.J.F. approved final version of manuscript.