The present study investigated HR and AP variability in patients with PCS with symptoms of cardiovascular disorders compared to control subjects evaluated before the Covid-19 pandemic. In addition, 10 out of 16 patients with PCS were reassessed after 6 months.
Besides the cardiovascular variability at rest, the subjects of the present study were also evaluated during HUTT, a challenge to the cardiovascular system.
The analysis of HRV of patients with PCS at rest demonstrated an attenuation of the RMSSD and HF power of RR spectra, combined with a significant reduction of the occurrence of the 2UV pattern from symbolic analysis. Therefore, these findings suggest that patients with PCS exhibit a reduced vagal - parasympathetic - modulation of the heart at rest. Apropos, the patients with PCS on their first recording, as expected, showed higher basal HR compared to control subjects.
These findings are in line with previous observations from the literature17,18, suggesting that long Covid-19 has led to an impairment of parasympathetic function. Furthermore, it was also observed in the current study lower SpEn of RR Intervals in the patients with PCS. This observation is also in line with those published by Aliani et al.19, who showed a decrease in entropy related to the severity of Covid-19. Of note, Aranyó et al.18 stated that the imbalance of the cardiac autonomic modulation may explain, for instance, the inappropriate sinus tachycardia (IST) in patients with PCS, an outcome also observed in some patients from the current study exhibiting PCS.
Moreover, Leitzke et al.20 have pointed out that patients with an increased risk of a more severe Covid-19 showed a disturbed balance of the autonomic nervous system, particularly with impairment of vagal function21. Additionally, looking at the identification of a cut-off point value for HRV that is associated with elevated risk across a range of known risk factors, Leitzke et al.20 provided the first evidence that changes in RMSSD may be associated with elevated risk across a range of established cardiovascular risk factors.
However, the findings from the current study contrast with the observations from other studies in patients with a history of Covid-19, who found an increased RMSSD4,22 consistent with a parasympathetic overactivation1. Asarcikli et al.4 have also found an LF/HF ratio increase, which is consistent with sympathetic overactivity. On the other hand, when Salem et al.23 investigated the post-acute effect of SARSCoV-2 infection on cardiovascular autonomic activity in patients with PCS, who were exposed to the infection at least 3 months before, they concluded that despite several parameters of HRV being numerically reduced in these patients with PCS, they were not statistically significant.
It was also observed in the current study that the patients with PCS exhibited a LF power of HRV indicating that the sympathetic modulation of the heart was not altered at rest; however, the increase in the occurrence of 0V contradicts this observation, indicating an increased sympathetic modulation of the heart in these patients. It is notable that Asarcikli et al.4 found an increase of the LF/HF ratio, which is also consistent with sympathetic overactivity. Finally, Stute et al.2 observed an increase in resting sympathetic activity in young adults, who tested positive for SARS-CoV-2, when measuring muscle sympathetic nerve activity (MSNA).
The analysis of AP variability showed higher overall pressure variability, confirmed by the higher values of SD of systolic AP in patients with PCS. In addition, these patients also showed higher LF Power of AP spectra and higher occurrence of 0V patterns compared to their control counterparts. These findings strongly indicate an overactivity of vascular sympathetic modulation at rest in these patients15,24,25,26.
It is worthy of note that the literature displays few studies of blood pressure variability in Covid-19. Nevertheless, an imbalance of the autonomic nervous system has been suggested to determine the severity of Covid-1920,27. What is more, the data from the study of He et al.28 provided an important contribution to this notion; since they are considered within the context of the precise pathophysiology underlying the relationship between Covid-19 infection and day-to-day BP variability7. In line with this understanding, Li et al.6 observed greater variability of systolic arterial pressure in critically ill patients, when compared with their severe and discharged counterparts. This conclusion came from the investigation of day-by-day blood pressure variability, and its association with clinical outcomes (critical vs. severe and discharged), in hospitalized patients with Covid-196.
In addition, Nam et al.29 investigated the impact of blood pressure variability on the outcomes from Covid-19 patients displaying arterial hypertension. These authors Nam et al.29 concluded that high blood pressure variability in Covid-19 patients exhibiting arterial hypertension is significantly associated with in-hospital mortality.
Overall, the studies in the literature involving Covid-19 patients and blood pressure variability are mainly focused on the severity of the illness and the associated mortality; instead of the associated deterioration of the autonomic nervous system.
It should be emphasized that the literature is remarkably poor concerning investigating challenging maneuvers to the cardiovascular system, such as the HUTT with Covid-19. It is quite curious that Eldokla & Ali8 reported that most patients presenting long-Covid in their laboratory with orthostatic intolerance had no significant HUTT abnormalities; while only 3 patients met the criteria for Postural Orthostatic Tachycardia Syndrome (POTS).
It is well known that passive HUTT promotes graded changes in the sympathovagal balance30. Thus, the HUTT was used in the current study to characterize the derangement of the sympathovagal balance response of the heart and blood vessels in patients with PCS.
As expected, the time domain results demonstrated a significant reduction of the RMSSD during the HUTT in both control subjects and patients with PCS; while patients with PCS displayed a noticeable attenuation of this response compared to their control counterparts. As well as this, an expected decrease was also observed concerning the HF power of RR interval spectra and a reduction of 2UV pattern in control individuals, but not in patients with PCS. Likewise, an expected increase of the LF power of RR intervals was observed with an increase in the occurrence of 0V pattern in the control subjects, but not in patients with PCS during HUTT. These findings indicate a noxious effect of SARS-CoV-2, which probably affected the response of the sympathovagal balance elicited by HUTT in patients with PCS.
SpEn is a non-linear index of heart rate dynamics, which describes the complexity and unpredictability of RR interval behavior. It is linked to the vulnerability of the development of detrimental conditions such as atrial fibrillation and/or life-threatening ventricular arrhythmias31. Likewise, other non-linear indices of HRV, such as the role of the autonomic modulation of the heart in the genesis of HRV entropy is not defined. Nevertheless, when Silva et al.32 examined the SpEn at multiple time scales with pharmacological blockade of cardiac autonomic receptors in rats, they found that entropy at short scales reflects vagal modulation of HR. In contrast, at long time scales, it would be associated with both sympathetic and parasympathetic cardiac modulation32. Of note, other studies in the literature corroborate this interpretation33.
In line with the other findings of the present study, SpEn was lower in patients with PCS, when compared to control subjects; and was not reduced during HUTT in these patients. Therefore, the results of SpEn strongly suggest a derangement in cardiovascular modulation in patients with PCS with cardiovascular symptoms.
Taking into account that the LF power of pressure spectra, as well as the occurrence of 0V from symbolic analysis, did not increase during HUTT in patients with PCS, as it did in control subjects; this strongly suggests that the noxious effect of SARS-CoV-2 on cardiac control also affects the modulation of vascular smooth muscle in patients with PCS.
The results of HRV regarding the sympathovagal modulation of the heart from patients with PCS at the reassessment period, i.e., 6 months after the first recording, demonstrated that the RMSSD did not return to the values shown by the control subjects, contrasting with the data obtained in the frequency domain as well as the symbolic analysis. These last indices indicate that the imbalance of the sympathovagal cardiac modulation was normalized over 6 months.
However, these findings contrast with the observations from other studies4,17,18,22, which indicated that long Covid-19 exhibits an attenuation of the parasympathetic function.
Moreover, it was observed in the current study that the LF Power of HRV was similar in patients with PCS and control subjects at either the first recording or reassessment. These findings contrast with the occurrence of 0V - symbolic analysis - which was exacerbated during the first recording, but returned to normal at the reassessment period. Taken together, these findings indicate a normal sympathetic modulation of the heart within 6 months in patients with PCS. These findings are in line with the observations from Salem et al. 23, who investigated the post-acute effect of SARSCoV-2 infection on cardiovascular autonomic activity, reactivity, and sensitivity, in patients who had the infection at least 3 months before. These authors observed that these patients displayed several parameters of HRV without significant changes.
It was also detected in the current study that the patients with PCS exhibited an increased occurrence of 0V - symbolic analysis - at the 1st recording, which is coherent with the notion of an increased sympathetic modulation of the heart in these patients. Of note, this parameter was back to normal by the reassessment period, indicating a recovery of the sympathetic modulation of the heart under the circumstances.
The AP variability from patients with PCS demonstrated that the SD and the occurrence of 0V patterns of systolic AP - symbolic analysis - recovered to normal levels by the reassessment period. These findings indicate that the sympathetic modulation of the blood vessels in patients with PCS was back to normal when the three indices, i.e., SD (Time Domain), LF Power of AP spectra (Spectral Analysis), and the occurrence of 0V patterns - Symbolic Analysis - were taken into account at the time of reassessment.
As stated before, the literature offers few blood pressure variability studies in Covid-19 patients. Nevertheless, an autonomic nervous system imbalance has been reported to determine the severity of Covid-1920,27. In line with this understanding, Li et al.6 observed greater variability of AP in critically ill patients - compared with the severe and the discharged counterparts - when investigating day-by-day blood pressure variability and its association with clinical outcomes (critical vs. severe and discharged) in hospitalized patients with Covid-19. Thus, the results from the current study suggest a recovery of the sympathetic modulation of the vessels after 6 months.
The PSC patients exhibited a normal response, i.e., similar to their Control counterparts during the HUTT when reassessed after 6 months. Moreover, when the LF Power and the 0V% were taken into account, the patients with PSC exhibited, when reassessed after 6 months, a similar response compared to their control counterparts. These data not only indicate that during the HUTT there has been an increase in the sympathetic modulation of the blood vessels, but they also indicate that the sympathovagal balance of the vessels was back to normal within a 6-month time frame.
In conclusion, the set of changes found in the HR and BP variability indices in patients with PCS suggests an autonomic dysfunction, with sympathetic predominance, in these individuals. The marked impairment of the autonomic control of the heart and vessels could lead to a higher risk of life-threatening cardiovascular events. However, one of the major findings of the present study was that the patients with PCS, who underwent the reassessment of the parameters studied, demonstrated that the noxious effect of the Post-Covid Condition related to these findings tends to fade away over time.
The limitation of the current study is that not all PCS patients submitted to the First Recording returned for the Reassessment investigation, i.e., 10 out of 16 PCS patients returned for the Reassessment investigation.