Nature Cardiovascular Research nature cardiovascular research https://doi.org/10.1038/s44161-023-00414-8 Review article Cardiovascular effects of the post-COVID-19 condition Erin Goerlich 1 , Tae H. Chung 2 , Gloria H. Hong 1 , Thomas S. Metkus 1 , Nisha A. Gilotra 1 , Wendy S. Post 1 & Allison G. Hays 1 Throughout the COVID-19 pandemic, the new clinical entity of the post- COVID-19 condition, defined as a multisystemic condition of persistent symptoms following resolution of an acute severe acute respiratory syndrome coronavirus 2 infection, has emerged as an important area of clinical focus. While this syndrome spans multiple organ systems, cardiovascular complications are often the most prominent features. These include, but are not limited to, myocardial injury, heart failure, arrhythmias, vascular injury/thrombosis and dysautonomia. As the number of individuals with the post-COVID-19 condition continues to climb and overwhelm medical systems, summarizing existing information and knowledge gaps in the complex cardiovascular effects of the post- COVID-19 condition has become critical for patient care. In this Review, we explore the current state of knowledge of the post-COVID-19 condition and identify areas where additional research is warranted. This will provide a framework for better understanding the cardiovascular manifestations of the post-COVID-19 condition with a focus on pathophysiology, diagnosis and management. The widespread study of COVID-19 has led to the discovery of various underlying pathological mechanisms and clinical sequelae 1 . Although primarily a respiratory pathogen, SARS-CoV-2 is now known to cause multiorgan dysfunction with systemic inflammation ranging from asymptomatic to fatal. The increasingly common condition following acute infection has been described in variable terms including long COVID-19 syndrome, long COVID, post-COVID-19 condition and post- acute sequelae of COVID (PASC) 2 . One common definition of the post- COVID-19 condition is a multisystemic condition of persistent, relapsing or new symptoms following an acute SARS-CoV-2 infection 3 . To date, there are over 23,000 publications regarding the post-COVID-19 con- dition. Many of these focus on defining the syndrome and identifying the patient populations most affected 4 . Other publications have delved into the molecular mechanisms at play and hypotheses surrounding the pathophysiology underlying clinical manifestations 5 . There has been considerable progress in attempting to determine the natural history of this syndrome and potential treatment approaches; however, many patients remain symptomatic years later and are considered to have a chronic health condition. This Review will provide a detailed overview into the currently known cardiovascular effects of the post-COVID-19 condition along with proposed management and future directions for this syndrome 4 Acute infection with SARS-CoV-2 is most classically marked by a febrile upper respiratory illness that commonly causes pneumonia and can lead to widespread organ dysfunction in severe cases; however, the infection can present in a multitude of ways 6,7 . In general, charac- teristics of patients found to be at higher risk of severe infection and COVID-19-related mortality include increasing age, male sex, minority race/ethnicity, a variety of comorbid medical conditions, obesity, active smoking, unvaccinated individuals, those with respiratory failure requiring mechanical ventilation and/or multisystem involvement, as well as those requiring intensive care 8–12 . Similarly, studies have shown that older patients with comorbidities are at higher risk for delayed recovery 13 . The immediate clinical manifestations of COVID-19 can affect nearly all organ systems and may include pneumonia, hypoxic respiratory failure, myocarditis, thromboembolism, stroke, acute myocardial infarction, acute kidney or liver failure, vasculitis and sev- eral immune phenomena 14–19 . While the majority of these processes are Received: 2 May 2023 Accepted: 13 December 2023 Published online: xx xx xxxx Check for updates 1 Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, MD, USA. 2 Department of Physical Medicine and Rehabilitation and Department of Neurology, The Johns Hopkins University, Baltimore, MD, USA. e-mail: ahays2@jhmi.edu Nature Cardiovascular Research Review article https://doi.org/10.1038/s44161-023-00414-8 and demographics, certain groups appear to be at higher risk includ- ing females, older patients, individuals who smoke and those with higher body mass index 8 . Additional risk factors include a variety of comorbid conditions, including individuals who required intensive care during their acute COVID-19 condition, and those with early pandemic variants, recurrent infections and incomplete vaccination status 3,8 (Table 1). The recently published prospective observational cohort as part of the National Institutes of Health Researching COVID to Enhance Recovery (RECOVER) Initiative proposed a scoring system to help identify patients with the post-COVID-19 condition. They identified 12 important symptoms among patients 6 months out from index infection: post-exertional malaise, fatigue, brain fog, dizziness, gastro- intestinal symptoms, palpitations, changes in sexual desire/capacity, loss/change in smell or taste, thirst, chronic cough, chest pain and abnormal movements 3 (Table 1). Although over 200 symptoms have been reported in the post-COVID-19 condition, these appear consist- ent with the most frequent complaints in affected individuals. This study importantly notes that there is great heterogeneity in symp- toms, and distinct phenotypes likely exist within all patients with the post-COVID-19 condition. Among the cardiovascular phenotypes proposed by the American College of Cardiology practice guideline document, the population with overt cardiovascular disease after COVID-19, deemed PASC-CVD, tend to be older with traditional cardio- vascular risk factors and comorbidities. These patients are more com- monly found to have demonstrable myocardial dysfunction, ischemia and/or inflammation. Those with cardiovascular symptoms (such as chest pain and palpitations) while lacking clear disease on diagnostic testing, termed PASC-CVS, are classically younger and healthier at baseline 22 . These represent two separate populations in terms of likely pathophysiology and thus proposed management. A multidisciplinary approach involving various specialists such as cardiologists, pulmonologists, neurologists, rheumatologists, psy- chiatrists and infectious disease experts is often utilized to diagnose the post-COVID-19 condition. Initial diagnostic evaluation typically includes laboratory testing (such as complete blood count, basic meta - bolic panel, troponin, pro-brain natriuretic peptide and C-reactive protein), electrocardiogram and echocardiogram (Table 1). Based on the type and severity of patients’ symptoms and results of the initial testing, additional studies such as cardiac magnetic resonance imaging recoverable, the post-COVID-19 condition is subsequently diagnosed when a patient has unresolved acute illness, relapsing symptoms or incident symptoms occurring after acute COVID-19. The time course of this condition is variable. The World Health Organization developed a clinical case definition in 2021 of the post-COVID-19 condition as that which occurs in individuals with presumed or confirmed SARS-CoV-2 infection, usually 3 months from the onset of symptoms, lasting at least 2 months, and unable to be explained by other diagnoses 20 . A more recent and widely accepted definition uses a timeline of 30 days after infection to classify the post-COVID-19 condition 3 The components of the post-COVID-19 condition specifically relevant to the cardiovascular system that will be focused upon in this Review include myocardial injury, heart failure, thrombosis, dysauto- nomia and arrhythmias (Fig. 1) 21 . Special distinction has been given to two subpopulations of patients with a post-COVID-19 condition by the American College of Cardiology in their 2022 Expert Consensus Deci- sion Pathway on Cardiovascular Sequelae of COVID-19 in Adults: those with cardiovascular risk factors and/or preexisting disease who develop a broad range of cardiovascular conditions versus patients with car- diovascular symptoms who lack objective evidence of cardiovascular disease 22 . The distinction is felt to be important regarding underlying pathophysiology and treatment and will be discussed further. Patients are being increasingly referred to cardiologists for management of the post-COVID-19 condition; therefore, a solid understanding of the mechanisms and treatment options is imperative for cardiovascular care providers. Diagnosis The post-COVID-19 condition can involve nearly every organ system and include dozens of symptoms. The most common non-cardiovascular effects reported include neurologic, psychologic, renal, respiratory and gastrointestinal dysfunction 2 . There is often a complex interplay between affected systems and resultant patient symptoms. Nonspecific complaints can include fatigue, dizziness, abdominal pain and memory loss. Certain underlying mechanisms such as systemic inflammation may explain the overlapping and vague symptoms. The post-COVID-19 condition has shown to be a highly variable disease process in terms of populations affected, time course, symptomatology and prognosis. Although the post-COVID-19 condition can be seen in nearly all ages Endothelial dysfunction/vascular thrombosis • Microclots • Angiogenesis upregulation • Hyperactive immune response Heart failure • Direct viral invasion • Cytokine release • Myocyte necrosis/fibrosis Myocardial injury • Hypoxemia • Hyperinflammatory state • Thromboembolism • Microvascular injury Arrhythmia • Inflammatory cytokine release • Persistent immune dysfunction • Myocardial fibrosis • Gap junction dysfunction Dysautonomia • Autoimmunity • Sympathetic dysfunction and hyperfunction • Abnormal neurologic signaling Fig. 1 | Cardiovascular complications in the post-COVID-19 condition. The major categories of cardiovascular sequelae seen in the post-COVID-19 condition and their respective mechanisms. Nature Cardiovascular Research Review article https://doi.org/10.1038/s44161-023-00414-8 (MRI), coronary angiography, ambulatory rhythm monitor, chest imag- ing and pulmonary function tests may be pursued 22 Although the cardiovascular complications of the post-COVID-19 condition are highly publicized, the sequelae from this virus are not particularly unique. Cardiovascular effects including myocardi- tis have been long described following other viral illnesses such as influenza and Epstein–Barr virus 23,24 . Similarly, myalgic encephalomy- elitis/chronic fatigue syndrome (ME/CFS) has several parallels to the post-COVID-19 condition and is hypothesized to arise after a percent- age of Epstein–Barr virus and other viral infections 25 . However, the mortality rate and incidence of vascular complications is far greater in COVID-19. Pathophysiology The currently known pathophysiology underlying many of the car- diovascular complications of the post-COVID-19 condition can be grouped into those involving immune dysregulation and inflamma- tion, endothelial dysfunction, microvascular injury and neurological signaling dysfunction 26–28 . Patients with the PASC-CVD phenotype are more likely to have endothelial dysfunction, microvascular injury and inflammation underlying their post-COVID-19 condition, while those with PASC-CVS tend to have more from immune dysregulation and neurological signaling dysfunction in addition to inflammation 22 Immediate cardiovascular effects of COVID-19 are often thought to be caused by direct cytotoxic injury with viral cell entry via the angioten- sin-converting enzyme 2 receptor or via downstream inflammation and cytokine release 26,29 . Hyperactivation of the immune system can induce endothelial dysfunction and immunothrombosis, further leading to microthrombotic complications, which can affect numerous organ systems by direct and indirect mechanisms 2,28 . Studies of patients with the post-COVID-19 condition have found plasma microthrombi in addi - tion to decreased capillary density many months after acute infection, which support a hypothesis of long-term vascular dysfunction 30,31 Furthermore, vascular activation biomarkers have been identified in individuals with the post-COVID-19 condition with angiogenesis pro- teins ANG-1 and P-SEL being highly sensitive and specific for predicting long COVID status 32 Ongoing inflammatory marker elevations have been detected in individuals with the post-COVID-19 condition suggesting a role of immune dysregulation pathways 2 . This is particularly relevant in the subpopulation of patients with PASC-CVS who typically lack cardio- vascular disease at baseline. In the case of autonomic dysregulation, abnormal signaling in neurological pathways has been suggested as an underlying mechanism for this common post-COVID-19 condi- tion manifestation 33 . There are also downstream effects of COVID-19 that secondarily impact cardiovascular disease. Patients recovered from COVID-19 have been found in multiple studies to have incident diabetes mellitus and hypertension as well as exacerbation of the disease for those with a preexisting diagnosis 34–36 . This undoubtedly contributes to increased risks of heart failure, atherosclerosis, atrial arrhythmias and endothelial dysfunction. Ultimately, further studies are needed to fully elucidate the major mechanisms involved in spe- cific symptom clusters of the post-COVID-19 condition to help guide treatment strategies. POTS Since the start of the COVID-19 pandemic, postural orthostatic tachy- cardia syndrome (POTS) has been increasingly recognized among individuals who develop chronic symptoms after recovering from acute COVID-19 infection, particularly those with the PASC-CVS phenotype described above. Initially, a few case reports emerged in which POTS was observed immediately after the resolution of acute COVID infection 37–44 As the pandemic continues, several studies have investigated auto- nomic function using various tests, including the head-up tilt-table test (HUTT), providing further evidence of autonomic dysfunction in the post-COVID-19 condition 45–58 (Table 2). However, the prevalence of POTS among individuals with the post-COVID-19 condition varies widely across studies, as not all patients meet the criteria for POTS on a tilt-table test. Nonetheless, their clinical symptoms are essentially indistinguishable, with most patients experiencing orthostatic intoler- ance during the HUTT. It is important to note that the reproducibility of the HUTT is moderate to poor in patients without structural heart disease 59–61 . Therefore, the actual prevalence of POTS is likely much higher than reported thus far. A recent meta-analysis of published studies on cardiovascular autonomic dysfunction following COVID- 19 infection revealed that the most common diagnosis in the post- COVID-19 condition (defined as symptom persistence for >28 days) was POTS 62 Typical symptoms of POTS include chronic fatigue, dizziness, palpitations, pre-syncope and brain fog, among many others, and these symptoms are often debilitating. POTS is defined by the presence of the above symptoms that last longer than 3 months and a sustained heart rate increase of at least 30 beats per minute (40 beats per minute for pediatric patients) or a heart rate of 120 beats per minute or more within 10 min of active standing or during the HUTT in the absence of orthostatic hypotension while reproducing the typical symptoms. POTS is a clinical syndrome, not a disease, with potentially heteroge- neous etiologies. The COVID-19 pandemic and increasing incidence of POTS in patients with the post-COVID-19 condition may offer insights to the underlying mechanisms at play. When diagnosing POTS, it is important to recognize the patterns of symptoms, and the HUTT is not always necessary to establish the diagnosis if other conditions that mimic POTS, such as pulmonary embolism, interstitial lung dis- ease or cardiac arrhythmia, have been ruled out. The HUTT should be considered as supporting evidence for POTS, rather than the sole diagnostic factor. The underlying mechanism of POTS is not well understood. Inter- estingly, evidence of both sympathetic dysfunction and sympathetic hyperfunction can be found in various literature sources 63–71 . In the peripheral nervous system (PNS), multiple studies have demonstrated evidence of vasomotor and sudomotor dysfunction at the post-gangli- onic level of the sympathetic nervous system. This dysfunction leads to orthostatic intolerance, brain fog, blood pooling and inadequate temperature regulation. Furthermore, impaired peripheral vasomo- tor function reduces cardiac preload, resulting in symptoms such as fatigue, exercise intolerance and exertional dyspnea 72 . In the central nervous system (CNS), various studies have shown intact or exagger- ated baroreflex function in patients with POTS. Consequently, the Table 1 | Clinical overview of the post-COVID-19 condition Demographics Symptoms Signs Diagnostic testing • Severe acute COVID-19 • Older age • Female • Higher BMI • Tobacco use • Comorbid conditions a • Immunosuppression • Preexisting mental health diagnoses • Fatigue • Post-exertional malaise • Chest pain • Palpitations • Brain fog • Gastrointestinal symptoms • Dizziness • Changes in sexual desire/ capacity • Loss/change in smell or taste • Thirst • Chronic cough • Abnormal movements • Tachycardia • Tachypnea • Orthostatic hypotension • Reduced muscle strength • Cognitive dysfunction • Musculoskeletal point tenderness to palpation • CBC • CMP • ProBNP • Troponin • CRP • EKG • Echocardiogram • Chest CT • PFTs • CPET • Ambulatory EKG monitoring • Tilt-table test • Cardiac MRI BMI, body mass index; CBC, complete blood count; CMP, complete metabolic panel; ProBNP, prohormone brain natriuretic peptide; CRP, C-reactive protein; CT, computed tomography; PFT, pulmonary function test; CPET, cardiopulmonary exercise testing. a Including asthma, chronic obstructive lung disease, diabetes and ischemic heart disease. Nature Cardiovascular Research Review article https://doi.org/10.1038/s44161-023-00414-8 reduced cardiac preload triggers a hyperadrenergic reaction, charac - terized by tachycardia, to maintain cerebral blood flow through the baroreflex. While this hyperadrenergic reaction compensates for the reduced cardiac preload, the heightened sympathetic nervous system activity itself gives rise to uncomfortable and debilitating symptoms, including disturbed sleep, anxiety, decreased appetite, indigestion, chronic nausea and constipation. In summary, patients with POTS experience both sympathetic dysfunction in the PNS and compensa- tory sympathetic hyperactivity in the CNS (Fig. 2). Individuals with the post-COVID-19 condition have been specifically studied and found to have reduced autonomic function, as evidenced by lower heart rate variability and other ambulatory electrocardiogram (EKG) metrics 73,74 The presence of both sympathetic dysfunction and hyperfunction in POTS poses unique challenges for clinicians. For instance, aggressive management of hyperadrenergic symptoms can exacerbate vasomo- tor symptoms, and vice versa. Therefore, when considering pharma- cological management of POTS symptoms, it is essential to carefully consider the paradoxical nature of the underlying physiology and to avoid polypharmacy if possible. Currently, there are no treatments that have been shown to restore autonomic nerve dysfunction in POTS. The primary treatment approach aims to increase blood volume to support vasomotor function. Although volume expansion does not provide disease-modifying effects in POTS, it can alleviate many debilitating symptoms. In the early stages of treatment, it is crucial to establish realistic and functional goals, as volume expansion therapy requires active patient participation, including lifestyle modifications, frequent medication adjustments, dietary changes and long-term rehabilitation while offering only limited benefits. There is an immediate and pressing need for research across vari- ous aspects of POTS. One research gap of high priority is the identifica- tion of the autoimmune subset of POTS, as it could pave the way for the development of disease-modifying treatments utilizing commercially available immune-modulating drugs. The COVID-19 pandemic has presented a unique opportunity to potentially uncover autoimmune markers, thanks to numerous research cohorts that have been tracking phenotypes following COVID-19 infection longitudinally. Currently, there is an ongoing phase 2 clinical trial for post-COVID POTS that involves the use of a neonatal fragment crystallizable (Fc) receptor Table 2 | POTS studies in the post-COVID-19 condition First author (type of study) Population Description 1. Wallukat et al. 45 (retrospective study) Blood sera of 31 patients after recovery from acute COVID-19 infection (2 of 31 were symptom free) 7 patients had POTS. All 31 investigated patients had between 2 and 7 different functionally active autoantibodies targeting G-protein-coupled receptors. 2. Buoite et al. 46 (retrospective study) Patients who were referred to a post-COVID-19 clinic between 15 February 2021 and 15 May 2021 Active stand test suggested the prevalence of orthostatic hypotension in 13.8% of the sample, while POTS was found in none of the participants. 3. Shouman et al. 47 (retrospective study) 27 patients with confirmed history of COVID-19 infection were referred for autonomic testing between March 2020 and January 2021 17/27 (63%) patients had abnormalities in autonomic function testing. The most common autonomic presentation was orthostatic intolerance. 22% of patients fulfilled the criteria for POTS. 4. Campen et al. 48 (case–control study) 10 patients with long COVID seen at a clinic 10 of 10 (100%) patients had POTS on the tilt-table test. 10 of 10 (100%) patients also had a substantial reduction in cerebral blood flow on Doppler ultrasound. 5. Novak et al. 49 (retrospective study) 9 adult patients with PASC who were referred to an autonomic laboratory 3 of 9 patients with PASC had POTS. All 9 patients had an abnormal reduction of cerebral blood flow during the tilt. Autonomic complaints were not different between PASC and POTS. 6. Jamal et al. 50 (prospective, observational study) Patients with PASC who presented with autonomic symptoms. 24 patients underwent full autonomic testing. Of them, 23 had orthostatic intolerance on the HUTT, with 4 demonstrating POTS, 15 had provoked orthostatic intolerance after nitroglycerin, 3 had neurocardiogenic syncope and 1 had orthostatic hypotension. 5. Eldokla et al. 51 (retrospective study) 14 patients who were referred to autonomic testing 3 of 14 (21.4%) patients were confirmed to have POTS. None had orthostatic hypotension. 8 of 14 (57%) patients demonstrated the symptoms of orthostatic intolerance. 6. Campen et al. 52 (retrospective study) 29 patients with long COVID symptoms referred for evaluation of orthostatic intolerance and/or dysautonomia Prevalence of POTS is reduced with increased duration of long COVID, but abnormal cerebral blood flow persists. 7. Kwan et al. 53 (retrospective chart analysis) Electrical health record data of all the patients who had at least one COVID-19 vaccination dose ( n = 289,662) and with documented COVID-19 infection ( n = 20,390) from 2020 to 2022 There is evidence of POTS-associated diagnoses occurring more frequently after COVID-19 vaccination. However, the rate of new POTS diagnoses after vaccination was much less frequent than that of new POTS diagnoses after COVID-19 infection. 8. Chung et al. 54 (retrospective study) 13 consecutive patients with PASC who were referred to an autonomic laboratory 7 of 11 patients had POTS on a tilt-table test. Other autonomic function test results are indistinguishable between POTS and PASC. 9. Eslami et al. 55 (single-center, cross-sectional observational study) 60 consecutive patients who recovered from severe or critical COVID-19 Orthostatic hypotension was detected in 29 of 60 (48.3%) and 10 of 60 (16.7%) patients at the time of hospital discharge. Two months later, the symptoms were resolved in 8 of 10 patients with POTS (80%) and 26 of 29 patients with orthostatic hypotension (89.7%). 10. Hira et al. 56 (descriptive study) 70 PASC patients who were recruited from a COVID clinic 73% of all patients with PASC met the criteria for at least one cardiovascular autonomic abnormality. 30% of patients with PASC had POTS and 2.9% had orthostatic hypotension. 11. Zanin et al. 57 (prospective study) 16 patients with long COVID who were consecutively referred to an autonomic laboratory with 16 age-matched healthy volunteers 37% of long COVID patients had at least one abnormal autonomic test result. 31.2% of long COVID patients had parasympathetic abnormalities, while 18.8% of them had sympathetic abnormalities. Only 12.5% met the criteria for POTS. 12. Gonzalez-Hermosillo G et al. 58 (prospective study) 23 patients who previously had COVID-19 pneumonia and developed PASC and 32 healthy controls without a history of COVID-19 infection 34.7% had exaggerated orthostatic blood pressure on the HUTT, compared to 6.4% in healthy controls. None met the criteria for POTS. Nature Cardiovascular Research Review article https://doi.org/10.1038/s44161-023-00414-8 antagonist 75 . Additionally, multiple research projects are underway to investigate viral persistence, microclots and neuroinflammation as underlying factors in the post-COVID-19 condition or post-COVID POTS. Myocardial injury Biomarker evidence of myocardial injury is common in acute COVID-19, typically manifested by elevated circulating levels of troponin. This is important because although acute myocardial injury may resolve fully, injury may persist in some patients or yield scarring, which may manifest as long-term sequelae of COVID-19 infection. The incidence of myocar- dial injury among patients with acute COVID-19 infection depends on the specific assay used, study population and phase of the pandemic; rates of up to 36% have been reported 76 . However, only up to 7% of individuals with acute COVID had chronic myocardial injury in one study 77 Myocardial injury may result from general critical illness facets of acute COVID-19 including hypoxemia and shock, for example 78 . Cardiac structural pathology may also contribute including ventricular systolic and diastolic dysfunction, pericardial effusion and valve disease, which may be preexisting and exacerbated by COVID or may be de novo 79,80 Other mechanisms of myocardial injury include hypercoagulabil- ity leading to microthrombi or macrothromboses including venous thromboembolism and arterial thromboembolism and a hyperinflam- matory state 11,81,82 Multimodality imaging techniques including cardiac magnetic resonance (CMR) imaging and echocardiography shed light on the longer-term implications of myocardial injury associated with COVID-19 (refs. 83,84). Individuals with persistent fatigue or dyspnea after COVID infection had CMR and were compared to controls. Approximately 7% of individuals with chronic COVID symptoms had late gadolinium enhance- ment on CMR compared to zero controls 85 . Such abnormalities are also observed on CMR in individuals with persistent COVID symptoms who did not have initial biochemical myocardial injury 86 . This suggests that our current understanding of the causal pathway between COVID infec- tion, myocardial injury, resolution or persistence of myocardial injury, subsequent imaging findings suggesting myocardial pathology and the presence or absence of persistent COVID symptoms is incomplete. For example, a case–control comparison of patients who were hospi- talized with COVID who did versus did not have myocardial injury was performed 87 . All patients underwent CMR, and the rate of structural cardiac abnormality was 61% in cases compared to 31–36% in controls. These abnormalities included 17% of cases with ventricular dysfunction versus 3–7% of controls and 13% of cases with infarction versus 2–7% of controls. Adverse event rates to 12 months occurred in 10% of cases and 6% of controls ( P = 0.7). Scar formation on MRI was a predictor of adverse outcomes, while troponin elevation itself was not 87 . This study and others illustrate the potential utility of CMR to quantify myocardial scarring in individuals with cardiac dysfunction after COVID-19 infec- tion; however, larger and longer-term terms are needed for accurate risk stratification of patients for adverse cardiovascular events. Overall, the cardiovascular outcomes after COVID-associated myocardial injury are variable and depend on the study population, mechanism of myocardial injury and the endpoint selected. Acute myocardial injury related to severe COVID requiring hospitalization or intensive care unit stay is associated with high short-term risk for mortality 88 . Chronic myocardial injury was associated with a nearly fourold increased risk for medium-term (6-month) mortality 77 . Mor- tality is not the only endpoint of importance to patients, and studies with patient-reported outcomes and functional outcomes are needed. Heart failure andmyocarditis Myocardial injury, as outlined above, may be associated with direct end-organ cardiac impact that can have important implications in the long-term cardiovascular sequelae of COVID-19. One cause of acute myocardial injury in the context of viral infection includes myocarditis 89,90 . Myocarditis is an inflammatory condition involving the myocardium, and can arise from a variety of etiologies including infections, toxins and immune diseases. Acute symptoms include chest pain syndrome, heart failure symptoms and palpitations or syncope in the setting of arrhythmias. Diagnosis is typically based on clinical presentation and a combination of diagnostic testing including cardiac biomarkers, CMR (using the modified Lake Louise Criteria) to identify signs of edema, fibrosis or hyperemia, and, in some cases, endomyo - cardial biopsy (using the Dallas Criteria) to identify histopathological evidence of myocardial inflammation 83,91–93 . However, caution has been given to using the modified Lake Louise Criteria with CMR to diagnose post-COVID-19 myocarditis due to existing definitions of myocarditis relying on evidence of focal areas of necrosis, while the pathology after COVID-19 is that of more heterogenous and diffuse inflammation. CMR in these patients thus will often show evidence of inflammatory phenomena without classical myocarditis 22 . Patients hospitalized for COVID-19 infection showed approximately 16 times the risk of myocar- ditis compared to those hospitalized for other reasons, according to a study by the Centers for Disease Control and Prevention 94 . Despite these findings, acute myocarditis in the setting of COVID-19 infection is an infrequently reported complication, with autopsy studies suggesting a much lower rate of true myocarditis. In a systematic review of stud- ies examining autopsied hearts after COVID-19 infection, among 277 cases the rate of histologically reported myocarditis was 7.2%; however, the investigators proposed a true prevalence of less than 2% given the diagnostic inconsistencies across included studies 95 Although COVID-19 often initially manifests as a respiratory ill- ness period, it may later manifest with multiorgan system involvement several weeks later. Although relatively rare, multisystem inflamma- tory syndrome may develop, which is a clinical syndrome occurring approximately 4 weeks after acute COVID-19 infection and characterized by fevers, laboratory evidence of active inflammation and end-organ involvement 96 . From a cardiac standpoint, it is characterized by an acute, fulminant myocarditis-like syndrome including heart failure and, in some cases, cardiogenic shock 97 . Patients are managed with intravenous corticosteroids and immunoglobulins as well as hemodynamic support, which may include mechanical circulatory support in severe cases 98 Increased sympathetic function • Anxiety • Palpitations • Shakiness • Hot flush • Low GI mobility • Sleep disturbance • Hyperhidrosis Decreased sympathetic function • Chronic fatigue • Brain fog • Orthostatic intolerance • Exercise intolerance • Post-exercise flare • Blood pooling • Anhydrosis Direct damage vs autoimmune inflammation to sympathetic ganglia and axons Central nervous system Peripheral nervous system SARS-CoV-2 Baroreflex compensatory reaction Fig. 2 | Pathophysiology of POTS in the post-COVID-19 condition. The pathophysiology underlying POTS can involve both sympathetic dysfunction in the PNS and compensatory sympathetic hyperactivity in the CNS. In the post-COVID-19 condition, this is hypothesized to occur secondary to direct SARS-CoV-2 viral invasion versus autoimmune and/or inflammatory injury of the nervous system. GI, gastrointestinal. Nature Cardiovascular Research Review article https://doi.org/10.1038/s44161-023-00414-8 The incidence of post-acute myocarditis or recurrent myocarditis in COVID-19 is not yet well defined. CMR studies of patients who have recovered from COVID-19 have reported upwards of 15% rates of myo- cardial abnormalities on delayed gadolinium enhancement imaging consistent with myocarditis, suggesting the possibility of longer-term subclinical myocardial sequelae 98,99 . Acute and subacute myocardial inflammation is known to increase the risk of future ventricular arrhyth- mias and cardiomyopathy due to development of cardiac fibrosis in other forms of myocarditis 100,101 . Future studies are needed to better understand these implications in COVID-19. However, it is reasonable to extrapolate current standards of myocarditis care to COVID-19, includ- ing exercise restrictions and cardioprotective medications 93,102 . These include prescribing beta blockers and angiotensin receptor blockers/ neprilysin inhibitors or angiotensin-converting enzyme inhibitors as tolerated. Pericarditis or myopericarditis, which can initially be respon- sive to anti-inflammatory therapies, carries the longer-term complica- tion of risk of recurrence and, therefore, affected individuals require continued monitoring, particularly when weaning off treatment. Whether clinically overt or subclinical, acute myocardial injury can lead to myocardial dysfunction and resultant cardiomyopathy from COVID-19 infection 80 . Causes of cardiomyopathy in the context of COVID-19 include stress cardiomyopathy, myocarditis, consequences of multisystem inflammatory syndrome and an acute coronary syn- drome mechanism 103 . Future longer-term studies of COVID-19-related myocardial injury will be needed to determine the risk of developing cardiomyopathy with ventricular dysfunction in individuals with acute COVID-19 myocardial injury. When there is concern for ventricular dys- function, an accurate assessment of ejection fraction including more sensitive markers of ventricular dysfunction such as global longitudinal strain should be obtained. Patient functional status using thorough heart failure symptom assessment should be addressed accordingly. For example, cardiopulmonary symptoms such as dyspnea (shortness of breath) may need to be further evaluated to distinguish between cardiac and pulmonary sequelae of COVID-19 infection, whereas heart failure-specific symptoms such as orthopnea (shortness of breath while lying flat) and bendopnea (shortness of breath when bending over) would prompt directed treatment with loop diuretics and guideline- directed medical therapies 104 . Right ventricular cardiomyopathy may occur after COVID-19 for a myriad of reasons, including advanced lung disease or pulmonary embolism leading to right ventricular strain 105 In these cases, individuals with right ventricular cardiomyopathy may not physiologically tolerate afterload reduction and beta blockade but may require mild diuretics. Individuals with reduced cardiac function require close monitoring and serial assessment to monitor for recovery. In those with persistent left ventricular dysfunction, an implantable cardioverter defibrillator may be indicated to prevent sudden cardiac death, based on current guidelines 104 Arrhythmias Acute infection with COVID-19 has been associated with notable increases in cardiac ectopy and arrhythmias, which can persist or pre- sent later in patients diagnosed with the post-COVID-19 condition 106–108 Sinus tachycardia is commonly seen in the post-COVID-19 condition and may be a secondary effect from or component of autonomic dysfunc- tion, deconditioning, hypoxia, heart failure or ongoing inflammation as described above. In addition, atrial and ventricular tachyarrhythmias, bradyarrhythmias and heart block have been described in the COVID-19 literature 106 . Aside from sinus tachycardia, the most common incident arrhythmia reported has been atrial fibrillation 107,109 . This often presents in the acute infectious period and more often in critically ill patients; however, analysis of the Veterans Health Administration data showed a higher incidence of cardiac dysrhythmias including atrial fibrillation in patients both 6 and 12 months after COVID-19 infection compared to control patients without COVID-19 (refs. 21,110–112). The relation of incident atrial fibrillation specifically with the post-COVID-19 condition remains unclear. Individuals diagnosed with the post-COVID-19 condi- tion very frequently report subjective palpitations and tachycardia, but diagnosis of true arrhythmia has been limited by a paucity of studies including ambulatory EKG monitoring in this population 113 . Reports of ventricular arrhythmias are largely limited to those hospitalized with acute COVID-19, with few studies reporting ambulatory EKG monitor- ing data in individuals with the post-COVID-19 condition. However, one study of patients 3 months after COVID-19 hospitalization with 24-h ambulatory EKG monitoring showed 5% of patients had nonsustained ventricular tachycardia and 18% had frequent premature ventricular contractions 114 . Mechanisms underlying cardiac arrhythmias in the setting of the post-COVID-19 condition are primarily thought to involve inflammatory cytokine release, persistent immune dysfunction, myo- cardial scarring and fibrosis, and potential gap junction dysfunction 101,113 In general, the treatment approach for cardiac arrhythmias in the post-COVID-19 condition is not different from the treatment of arrhythmias unrelated to COVID-19 and should be guideline based. Table 3 | Established and investigational treatments for the post-COVID-19 condition Cardiac agents Antivirals Anti-inflammatory agents Anti-fibrotic agents Respiratory agents Other pharmacological therapies Non-pharmacological therapies • Beta blockers • ACE inhibitors/ ARB/ARNIs • SGLT2 inhibitors • Ivabradine • Statins • Colchicine • DOACs • Favipiravir • Nirmatrelvir/ ritonavir (Paxlovid) • Remdesivir • Molnupiravir • Naltrexone • Baricitinib • Pentoxifylline • Fluvoxamine • Ibudilast • Imatinib • Infliximab • Cannabinoids • Melatonin • Pycnogenol • BC 007 • LAU-7b • AER002 • Anakinra • Pirfenidone • Nintendanib • Deupirfenidone • Montelukast • Bronchodilators • Lithium • Vortioxetine • Pimozide • Somatropin • Cyclobenzaprine • Temelimab • RSLV-132 • AXA1125 (endogenous metabolic modulator) • Vitamins • Oxaloacetate • DAOIB a • Human umbilical cord blood • Ampion • Rintatolimod • Amantadine • Probiotics • MCT oil • Testofen • FMT • Vagus nerve stimulation • Stellate ganglion block • Hyperbaric oxygen • Cognitive behavioral therapy • Cardiac rehab • Qigong • Bright light therapy • Low-carb