Impact of long COVID on the heart rate variability at rest and during deep breathing maneuver | Scientific Reports – Nature.com

The main findings of the current study were as follows: (1) at rest, patients with Long COVID presented altered time and non-linear index of HRV suggesting high HR, lower parasympathetic tone (rMSSD; SD1), lower variability of RR intervals (RR tri index) and total variability (SD2) as well as impaired fluctuation analysis with increased risk of sudden death (alpha 1) compared to controls; (2) patients with Long COVID responded to the M-RSA with an increase in time index of HRV, however this response were significantly lower compared to controls, reinforcing lower parasympathetic tone (rMSSD), lower variability of RR intervals (RR tri index) and lower HR dynamics.

Different methods of autonomic assessment have been used in contemporary literature (pupillometry, microneurography, negative lower body pressure, cold pressor test, Ewing protocol, Holter, etc.) however, their use in clinical settings is limited16. To our knowledge, no studies with Long COVID patients have investigated heart rate variability in different postures and M-RSA with the device Pro-Trainer 5 with POLAR software, an accessible tool both in terms of cost and practicality, in addition to presenting good accuracy both at rest and during exercise17. Our study is the first to use the Pro-Trainer and this is of great clinical relevance in the context of diagnosing autonomic dysfunction and cardiovascular risk.

Research has demonstrated COVID-19 not only affects the cardiovascular system in its acute phase but can have prolonged negative effects4. Most patients with COVID-19 recover completely without sequela, while some patients continue to have diverse symptoms, including autonomic dysfunction, for longer than 12weeks without an alternative diagnosis12,18. Long COVID symptoms of inappropriate palpitations, fatigue, orthostatic intolerance, dizziness, brain fog, nausea, anxiety, hyperhidrosis and syncope have been reported; there is currently a lack of evidence to indicate how long these autonomic symptoms will last9.

The mechanism of dissemination and development of COVID-19 in the human body, the immune system response, and the action of the virus on the Autonomic Nervous System (ANS), are obscure topics. Infection by the COVID-19 virus can generate inflammatory responses, once the immune system is active, which can lead to systemic damage19 including autonomic dysfunction mediated by the virus. Some studies have reported the association between autonomic dysfunction, neurotropism, hematogenous route or neuronal dissemination20,21. In this sense, the conflicting results in the current scenario refers to the increase in sympathetic activity at rest, which can lead to premature death22; contrasting with in young males and adult patients after COVID-19 showing increase of the parasympathetic nervous system activity demonstrating increased HRV indices than controls18. The findings of the current study differ from this concern [i.e., high HR, lower parasympathetic tone (rMSSD; SD1) and lower RR tri index and total variability (SD2) and increased risk of sudden death (alpha 1)]. We hypothesize that the differences found in our study are related to the clinical characteristics of the sample in relation to the literature [i.e., restricted to young men and/or young adults with a predominance of females, non-hospitalized and/or non-symptomatic patients12,18. These alterations in HR modulation trigger the emergence of cardiovascular diseases and inadequate adaptations of the ANS23, altering the homeostatic state of the body.

In this sense, patients with Long COVID may present with dysautonomia characterized by an imbalance of HRV, which is reflected in the band potencies of 0.150.4Hz13, and highlights that this dysautonomia could explain the persistent symptoms observed in patients with Long COVID13. In our study, we observed similar results with a lower complexity of HRV in patients with Long COVID [lower variability of RR intervals (RR tri index) and total variability (SD2) and impaired fluctuation analysis with increased risk of sudden death (alpha 1)] compared to controls.

In a Mayo Clinic study including patients with symptoms related to postinfectious autonomic dysfunction after COVID-19, 63% were found to have abnormal findings on standardized tests of autonomic function, such as cardiovagal function analyzing heart rate responses to deep breathing and the Valsalva maneuver12. The most common post-COVID-19 autonomic manifestation was orthostatic intolerance, and the remaining changes ranged from symptomatic postural orthostatic tachycardia to severe autonomic dysfunction24. Our observation and clinical data suggest that Long COVID patients have the highest Mean HR in the first few days and weeks of the convalescent phase. Regarding M-RSA, our findings suggest that patients after hospitalization had a worse cardiac autonomic modulation, with lower parasympathetic tone (rMSSD), lower variability of RR intervals (RR tri index) and lower HR dynamics. Autonomous innervation is the primary extrinsic control mechanism that regulates HRV and cardiac performance. Thus, this autonomic dysregulation likely represents the cause and effect of the different stages of COVID-19, the severe inflammatory system response syndrome (SIRS)11 and its compensatory anti-inflammatory response until Long COVID which can be influenced by frequency and depth of breathing. Many patients have restrictive pulmonary conditions after infection, but only 15% have restrictive and obstructive patterns25, and these changes can directly influence the ability to perform M-RSA. We highlight that M-RSA was performed in a controlled environment with a metronome, where there is control of the RR and the stimulus for deep breathing, providing good capacity to evaluate the parasympathetic modulation response.

We found that HRV is markedly impaired in the presence of Long COVID. Therefore, strategies aimed at improving autonomic control index can improve the cardiovascular risk in these patients, as well as symptomatological and pulmonary function changes, since the cardiorespiratory interaction is closely associated with peripheral oxygen supply and symptoms of persistent fatigue. These results, therefore, emphasize the multifactorial nature of the cardiopulmonary impairment present in these patients, associated with the symptomatological manifestations (i.e., dyspnea and feeling of fatigue) present in these patients. Our findings provide a rationale for improving fatigability with interventions aimed at improving cardiac and respiratory system autonomic control, through pharmacological and non-pharmacological measures aimed at reducing the cardiovascular risk in these patients. For example, cardiorespiratory rehabilitation can reduce muscle fatigue and improve cardiac autonomic function in other chronic conditions and has been the focus of numerous studies in patients with Long COVID. Future clinical trials on the impact of these interventions on cardiocirculatory and autonomic responses should look more carefully at the relevance of peripheral and respiratory muscle performance enhancing cardiac autonomic control in this patient population.

This was a single-center study with a small sample size. Asymptomatic patients with COVID-19 were not included. Patients' breathing characteristics and drug treatment were not measured and standardized in this study and the patients were referred to LARECARE in different times after COVID-19 infection. The differences in age and BMI between the Long COVID and control group can be considered a confounding factor, so we performed a linear regression analysis to verify the influence of both variables on the HRV indexes and no significant difference was found, demonstrating that age did not influence the main outcome of the study. Moreover, there was no follow-up of the patients over time to verify whether or not HRV dysfunction persists.

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Impact of long COVID on the heart rate variability at rest and during deep breathing maneuver | Scientific Reports - Nature.com