Cardiovascular and autonomic dysfunction in long-COVID syndrome and the potential role of non-invasive therapeutic strategies on cardiovascular outcomes

The paper addresses the growing problem of long-COVID and its cardiovascular and autonomic sequelae. Long-COVID is defined by the WHO as symptoms persisting for at least two months, usually starting three months after infection, that cannot be explained by another diagnosis. Common symptoms include fatigue, dyspnea, and cognitive dysfunction, with substantial adverse impacts on daily life. The authors highlight the urgent need to develop diagnostic and management strategies due to the anticipated healthcare burden. Large cohort evidence indicates significant increases—up to 2,000%—in risks for cardiovascular, pulmonary, metabolic, and neurological conditions within 1–6 months post-infection, with severity correlated to the acute phase. Dysautonomia, including a post-COVID Guillain-Barré-like syndrome (PCGBS), is implicated as a key mechanism linking chronic inflammation to sympathetic overactivity and cardiovascular/neurological dysfunction. The authors propose that restoring sympathovagal balance via cardiovascular rehabilitation programs (CRPs) could improve outcomes, and they summarize post-COVID cardiovascular consequences while encouraging evaluation and implementation of non-invasive techniques such as CRPs.

The review synthesizes findings from selected publications (2009–2022 for CRF/CRP/dysautonomia and 2020–2022 for long-COVID) focusing on epidemiology of long-COVID cardiovascular sequelae and non-invasive strategies to improve cardiovascular/autonomic outcomes. The authors note evidence of multi-organ involvement in COVID-19 and substantial prevalence of persistent symptoms. They emphasize studies linking dysautonomia and cardiovascular risks post-COVID, HRV as a diagnostic tool, and early reports on the potential of CRPs to improve quality of life and autonomic balance in long-COVID patients.

This is a brief narrative review. The authors searched for clinical studies from 2020 to 2022 using keywords including "long-COVID," "cardiovascular," and "autonomic/dysautonomia," and broader publications from 2009 to 2022 related to "cardiorespiratory fitness," "cardiovascular rehabilitation," and "dysautonomia." Studies were filtered for relevance to long-COVID cardiovascular sequelae epidemiology and feasibility of non-invasive strategies (e.g., CRPs) to improve cardiovascular and autonomic outcomes in clinical contexts. A total of 54 publications were selected, including epidemiological studies, clinical trials, scientific papers, and reviews.

- Long-COVID can affect up to 50% of COVID-19 patients post-acute infection; one study reported 87% had at least one symptom >2 months after infection. - Significant increases in risk (up to 2,000%) for cardiovascular, pulmonary, metabolic, and neurological conditions are observed 1–6 months post-infection, with graded risk by acute severity and mitigation by vaccination for myocarditis/pericarditis. - Cardiovascular outcomes elevated up to 12 months include cerebrovascular disease, dysrhythmias (AF, sinus tachy/bradycardia, ventricular arrhythmias), inflammatory heart disease (pericarditis, myocarditis), ischemic heart disease, heart failure, thromboembolism, and non-ischemic cardiomyopathy; effects are observed independent of baseline cardiovascular comorbidities. - Dysautonomia is prevalent; around 13% of acute and long-COVID patients may develop a post-COVID Guillain-Barré-like syndrome (PCGBS) characterized by microinflammation confined to autonomic fibers, leading to sympathetic overactivity with arrhythmogenesis, orthostatic hypotension, GI dysmotility, and cognitive issues. PCGBS has been reported among fatal complications of long-COVID. - Pathophysiologic hypotheses for long-COVID include: (1) endothelial dysfunction and hypercoagulability with microthromboses causing hypoperfusion and dyspnea; (2) persistence of viral particles provoking chronic inflammation and organ dysfunction; (3) long-term immune dysregulation/autoimmunity. - Diagnostic approaches: Heart rate variability (HRV) is a validated, non-invasive, quantitative measure of autonomic function and is superior to symptom surveys (e.g., COMPASS-31) for clinical assessment; AI-enhanced short ECG HRV can predict dysautonomia in post-COVID. - Therapeutic/management insights: Cardiovascular rehabilitation programs (CRPs) stimulate parasympathetic activity, reduce sympathetic tone, and improve CRF. In a pilot study in Japan (n=50, ages 65–74), a CRP achieved 90% adherence, reduced anxiety, improved autonomy, and enhanced quality of life. A case study of PCGBS showed marked improvements in dyspnea, fatigue, strength, autonomy, and function with personalized CRP. - Clinical guidance: ACC expert panel recommends cardiac function testing post-COVID, especially in high-risk adults. NICE recommends beta-blockers for angina/coronary syndromes/arrhythmias, supporting targeting sympathetic overactivity. Exercise training improves endothelial function, autonomic balance, and myocardial function in cardiac populations and may benefit long-COVID patients. - Pediatric considerations: MIS-C shares mechanisms with adult long-COVID (inflammation/oxidative stress), with cardiac dysfunction and dyspnea reported 2–6 weeks post-infection, but autonomic sequelae data and long-term pediatric follow-up are lacking.

The review argues that autonomic dysregulation—particularly sympathetic overactivity—mediates a significant portion of long-COVID cardiovascular and neurological sequelae. By identifying heightened cardiometabolic and neurovascular risks up to a year post-infection and linking them to dysautonomia and persistent inflammation, the paper supports targeted interventions that restore sympathovagal balance. HRV is proposed as a practical diagnostic tool to quantify autonomic dysfunction and guide management. Given the established benefits of CRPs in reducing sympathetic tone, improving parasympathetic activity, enhancing endothelial and myocardial function, and lowering hospitalization and risk in other cardiovascular conditions, the authors propose CRPs as feasible non-invasive adjuncts for long-COVID care. Early pilot and case data suggest improved adherence, autonomy, anxiety, and functional outcomes with CRPs in long-COVID, warranting broader implementation and study. Recognizing heterogeneity by age, severity of acute infection, and comorbidities, the paper emphasizes individualized assessment (including biomarkers and functional testing) to align therapies—exercise programs, pharmacologic control of sympathetic activity, and supportive education—to patient-specific phenotypes. The discussion underscores gaps in pediatric data and the need for standardized definitions and protocols.

Long-lasting cardiovascular sequelae of COVID-19 are partially mediated by autonomic nervous system alterations. Implementing cardiovascular rehabilitation programs and other non-invasive strategies in long-COVID management may help restore autonomic balance, improve functional capacity and quality of life, and reduce future disease burden. The authors call for focused studies to validate diagnostic tools like HRV and to establish the efficacy, protocols, and patient selection criteria for CRPs and exercise-based interventions in long-COVID populations, including dedicated research in children and adolescents.

- Long-COVID epidemiology and pathophysiology remain incompletely defined; causal mechanisms among endothelial dysfunction, viral persistence, and immune dysregulation are not fully established. - Evidence for CRPs in long-COVID is preliminary (pilot studies and case reports); large controlled trials are lacking. - Diagnostic tools like HRV, while validated for autonomic assessment, require further validation specifically for long-COVID phenotyping and prognostication. - Heterogeneity of long-COVID presentations complicates standardized management; confounding factors (age, comorbidities, severity of acute disease) may affect generalizability. - Pediatric data are limited, with insufficient long-term follow-up to characterize cardiovascular/autonomic sequelae and to design age-specific interventions.