Invited Review Article
Cardiovascular Manifestations of the Long COVID Syndrome
Marta Lorente-Ros, MD*, Subrat Das, MD†, Joseph Elias, MD*, William H. Frishman, MD‡, and
Wilbert S. Aronow, MD†
Abstract: While most coronavirus 2019 (COVID-19) survivors have had
complete resolution of symptoms, a significant proportion have suffered from
incomplete recovery. Cardiopulmonary symptoms, such as dyspnea, chest
pain, and palpitations are responsible for a substantial symptom burden in
COVID-19 survivors. Studies have revealed persistent myocardial injury with
late gadolinium enhancement and myocardial scar on cardiac magnetic reso-
nance in a significant proportion of patients. Evidence of myocardial edema,
active inflammation, left ventricular dysfunction, and right ventricular dys-
function, is limited to a minority of patients. Large observational studies of
COVID-19 survivors have indicated an increased risk of cardiovascular dis-
ease compared to the general population, including the risk of coronary artery
disease, cardiomyopathy, and arrhythmias. Management of long COVID is
focused on supportive therapy to reduce systemic inflammation. Patients with
high cardiovascular risk, namely, those who had cardiovascular complications
during acute illness, patients who have new onset cardiopulmonary symptoms
in the postinfectious period, and competitive athletes, should be evaluated by
a cardiovascular specialist. Management of cardiovascular sequelae is cur-
rently based on general expert guideline recommendations given the lack of
evidence specific to long COVID syndrome. In this review, we outline the
cardiovascular manifestations of long COVID, the current evidence support-
ing cardiac abnormalities in the postinfectious period, and the recommended
management of these patients.
Key Words: long COVID, post-acute sequelae of COVID-19, cardiovascular
disease
(Cardiology in Review XXX;XXX: 00–00)
A s of November 2022, the World Health Organization has reported
over 600 million cases of coronavirus disease 2019 (COVID-19),
including 6 million deaths. The COVID-19 pandemic has posed a
public health threat, overstrained healthcare systems across the
globe, and led to substantial economic losses.1
Among the extra-pulmonary organ damage of COVID-19,
cardiovascular manifestations were most encountered and recog-
nized as one of the leading causes of morbidity and mortality dur-
ing acute infection.2,3 While most COVID-19 survivors have had
complete resolution of symptoms, a significant proportion have suf-
fered from incomplete recovery, with persistent symptoms of dys-
pnea, chest pain, fatigue, palpitations, headaches, and brain fog. This
condition is known as long COVID syndrome.4 Notably, the chronic
sequelae of COVID-19 are not unique to the severe acute respiratory
From the *Department of Medicine, Icahn School of Medicine at Mount Sinai,
Mount Sinai Morningside Hospital, New York, NY; †Department of Cardiol-
ogy, New York Medical College, Westchester Medical Center, Valhalla, NY;
and ‡Department of Medicine, Westchester Medical Center and New York
Medical College, NY.
Disclosure: The authors declare no conflict of interest.
Correspondence: Wilbert S. Aronow, MD, Department of Cardiology, Westchester
Medical Center, New York Medical College, 100 Woods Road, Macy Pavilion,
Room 141, Valhalla, NY 10595. E-mail: wsaronow@aol.com.
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1061-5377/XX/XXX000-0000
DOI: 10.1097/CRD.0000000000000552
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syndrome coronavirus-2 (SARS-CoV-2). A similar phenomenon
has been described with SARS-CoV and Middle East respiratory
syndrome coronavirus, each of which was responsible for a global
epidemic. Similar to COVID-19 survivors, survivors of SARS-CoV
and Middle East respiratory syndrome coronavirus suffered from
persistent fatigue, dyspnea, reduced quality of life, and mental health
conditions, years after the acute illness.5
In the present review, we summarize the current definitions,
epidemiology, and clinical manifestations of long COVID syndrome.
We describe the cardiovascular symptoms of long COVID as well as
the objective evidence indicative of incident cardiovascular disease
after SARS-CoV-2 infection. Finally, we outline the proposed biolog-
ical mechanisms that lead to these findings, as well as the suggested
management of patients suffering from cardiovascular manifestations
after COVID-19.
DEFINITION AND EPIDEMIOLOGY OF LONG COVID
SYNDROME
Several terminologies and definitions have been used to refer
to the clinical syndrome characterized by persistent symptoms after
COVID-19. The terms include long COVID, long-haul COVID, post-
acute sequelae of COVID-19, and post-acute COVID-19 syndrome.6
The United Kingdom National Institute of Health and Care Excel-
lence has defined long COVID as the occurrence of symptoms last-
ing more than 4 weeks, following primary SARS-CoV-2 infection.
The National Institute of Health and Care Excellence further charac-
terizes 2 phases of long COVID based on the duration of symptoms:
ongoing symptomatic phase from 4 to 12 weeks (or subacute phase),
and post-COVID-19 syndrome after 12 weeks (or chronic phase).7
The World Health Organization uses the term post-COVID-19,
defined as “the condition that occurs in individuals with a history
of probable or confirmed SARS-CoV-2 infection, usually 3 months
from the onset of COVID-19, with symptoms that last for at least 2
months and cannot be explained by an alternative diagnosis.”6
The absence of a consensus definition for long COVID, the
differences in study design and population, and the variability in the
timing of patient evaluations across the various epidemiological stud-
ies have led to a significant discrepancy in the reported prevalence of
long COVID across and within many countries.8 The reported preva-
lence in the United States varies from 16% to 53%,9,10 in Europe from
5% to 77%,11–15 and in Asia from 16% to 76%.16–21
As is the case with the acute phase of SARS-CoV-2 infection,
long COVID affects multiple organ systems. Respiratory, cardiovascular,
neuropsychiatric, gastrointestinal, dermatologic, and musculoskeletal
symptoms have all been described as part of long COVID syndrome.4,22
The noncardiac manifestations of long COVID and their prevalence
among COVID-19 survivors are summarized in Table 1.18,21,23–29
FACTORS ASSOCIATED WITH LONG COVID
SYNDROME
Risk Factors
A better understanding of predisposing factors would enable
clinicians to identify subjects at higher risk for this condition and
Lorente-Ros et al Cardiology in Review  •  Volume XXX, Number 00, xxx XXX
TABLE 1.  Non-Cardiac Symptoms of Long COVID Syndrome
Organ System Symptoms Prevalence
Respiratory Dyspnea 6%–63% 21,23–25
Decreased exercise capacity 22%–29%18
Cough 2%–46%21,23–25
Neuropsychiatric Sleep difficulties 26%–93%18,23,28
Anxiety/depression 15%–42% 18,23,28
Loss of smell/taste 7%–22.7%18,24,25,28
Headaches 2%–18%18,21,24,25
Gastrointestinal and Diarrhea 2%–11%18,21,24,25
hepatobiliary
Dermatologic Rash 3%–8%18,25
Hair loss 22%18
Musculoskeletal Arthralgias 9%–27%18,24
Myalgias 2%–20%18,21,24,25
COVID indicates coronavirus disease 2019, MRI, magnetic resonance imaging.
to ensure adequate evaluation during outpatient follow-up. Several
factors have been associated with a higher risk of developing long
COVID symptoms in large observational cohorts. Women have a 1.5
higher risk of developing long COVID syndrome, as compared to
men.30–32 Patients who develop long COVID are older than COVID-
19 survivors with complete recovery.30–32 Low socioeconomic status,
poor mental health, smoking, asthma, and the presence of 5 or more
symptoms during acute infection all predispose patients to develop
long COVID.30–32 Diarrhea, anosmia, and lower initial SARS-CoV-2
IgG titers also appear to be predictors of long COVID.12 Myocardial
injury during index hospitalization is not only associated with in-hos-
pital mortality but is also a risk factor for long COVID syndrome.33
Most importantly, as seen in the acute phase of COVID-19,
obesity and metabolic syndrome are strongly associated with a high
risk of long COVID.30–32 It is well described that excessive and dys-
regulated inflammation is the hallmark of obesity and metabolic syn-
drome, driving multiorgan damage and resulting in more severe and
prolonged clinical presentations of both acute infection and long-
term symptoms.34
Whether the severity of the initial disease is a risk factor
for the development of post-COVID manifestations is a matter of
debate. Most studies have described disease severity, need for hospi-
talization, and intensive care unit (ICU) stay as risk factors for long
COVID.32,35,36 However, there is some evidence that cardiac magnetic
resonance (CMR) abnormalities may be independent of the initial
disease severity and present in low-risk cohorts from the commu-
nity.37–40 Specifically for cardiovascular outcomes, a large study
from a national Veterans Affairs (VA) database in the United States
found that all patients, including those who had not been hospitalized
during the acute infection, were at increased risk of cardiovascular
events at 1-year follow-up. In this study, the increased risk of nega-
tive cardiovascular outcomes was consistent across all subgroups of
age, sex, and cardiovascular risk factors, including obesity, diabetes,
hypertension, hyperlipidemia, and chronic kidney disease.41 This risk
was also consistent when examining only the cohort of patients with-
out preexisting cardiovascular disease.41 These results suggest that
cardiovascular disease after acute COVID-19 is an incident event in
patients without predisposing risk factors. However, the risk of nega-
tive cardiovascular outcomes was higher in patients who had been
hospitalized, with the highest risk being found in patients requiring
ICU admission. Patients who had not been hospitalized had an abso-
lute burden difference for any cardiovascular outcome of 29 per 1000
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Objective Findings
Decreased diffusion capacity, restrictive pulmonary physiology, ground glass
opacities, evidence of fibrotic changes on imaging, oxygen dependence18,25–27
MRI evidence of disruption of micro-structural and functional brain integrity29
persons at 1 year [HR: 1.39 (1.36–1.43)]. In hospitalized patients,
the burden difference was 163 per 1000 persons at 1 year [HR: 3.43
(3.21–3.66)]. In patients requiring ICU admission, the burden differ-
ence was 314 per 1000 persons at 1 year [HR: 6.19 (5.61–6.84)].41
Protective Factors
A global health approach with a focus on widespread vacci-
nation would be the most effective strategy to prevent incident-long
COVID syndrome. Vaccination has also been proposed as a protec-
tive factor. Various studies have investigated the potential protective
effect of COVID-19 vaccines on long COVID syndrome, but their
results were inconsistent. In an attempt to better understand this
effect, Gao et al.42 conducted a systematic review and meta-analysis,
which included 18 eligible studies. Analysis revealed that the vac-
cinated group had a 29% lower risk of developing long COVID when
compared to the unvaccinated group.42 Vaccination showed a protec-
tive effect in patients who received 2 doses, whether received before
or after SARS-CoV-2 infection, but not in those who received 1
dose.42 Treatment of hospitalized patients with remdesivir was asso-
ciated with a 35.9% reduction in the incidence of long COVID in a
single-center observational study.36 However, a proportion of these
patients also received other antivirals commonly used in the early
phases of the pandemic,36 raising the possibility that antiviral treat-
ment, in general, is what may reduce the incidence of long COVID.
CARDIOVASCULAR MANIFESTATIONS OF LONG
COVID
Cardiovascular complications during the acute phase of SARS-
CoV-2 infection have been well described. Hospitalized patients suf-
fered from acute myocardial injury, myocardial ischemia, pulmonary
and systemic thromboembolic events, right ventricular dysfunction,
and, less commonly, left ventricular dysfunction.3,43,44
More recently, research has raised concern about incident
cardiovascular disease in the postinfectious phase of SARS-CoV-2,
with emerging data on cardiac symptoms after discharge from the
index hospitalization, as part of the long COVID syndrome.35,45 A
large retrospective study from England followed 47,780 patients for
a mean of 140 days after discharge. The incidence of major adverse
cardiac events in this cohort (which included heart failure, myocar-
dial infarction, stroke, and arrhythmia) was 5-fold higher in patients
who recovered from COVID-19 compared to matched controls.46 In
Cardiology in Review  •  Volume XXX, Number 00, xxx XXX Cardiovascular Manifestations of Long COVID Syndrome
the United States, 153,760 patients from the national VA healthcare
database were followed for 1 year. Patients who had recovered from
COVID-19 were at increased risk of cardiovascular disease, includ-
ing stroke, myocarditis, pericarditis, ischemic and non-ischemic car-
diomyopathy, arrhythmias, and thromboembolic events.41
Patients with long COVID syndrome have reported cardiac
symptoms such as dyspnea, decreased exercise tolerance, chest pain,
palpitations, and orthostatic intolerance. In a descriptive cohort of
543 patients from Spain, dyspnea persisted in 47% of the patients
1 year after discharge, chest pain in 53%, and palpitations in 60%.47
Dyspnea can persist in up to 63% of patients 1-year post-infection,
with studies reporting a prevalence of dyspnea between 6% and
63%.19,21,23–25,47 Decreased exercise tolerance with abnormal 6-min-
ute walk test was found in 22–29% of patients recovered from acute
infection,18 with 50–55% of patients having a peak oxygen consump-
tion <80–85% of predicted values on cardiopulmonary exercise test-
ing.48–50 Chest pain is present in 5–22% of patients 2–6 months after
discharge from the index hospitalization.18,24 Palpitations have been
described in 9–20% of patients 2–7 months after discharge from the
acute infection.18,51 Other studies have reported a higher prevalence
of palpitations (up to 67%) and chest burning/pain (up to 53%), how-
ever, these were based on online surveys.52 Orthostatic intolerance
was reported in 14% of 180 patients evaluated 1–9 months after the
acute infection.53
Although the prevalence of these symptoms is widely variable
depending on the study population, the varying definitions of long
COVID, and the time of follow-up after the initial infection,4 it is
evident that patients who recovered from COVID-19 illness suffer
from a substantial burden of cardiovascular symptoms. The natural
history of these symptoms and their correlation with abnormalities
on cardiovascular testing needs further investigation.
Cardiovascular involvement in long COVID syndrome is not
limited only to subjective symptoms. Investigations in patients who
recovered from COVID-19 have revealed several abnormalities in
the postinfectious period. Objective findings in patients with long-
COVID syndrome have included evidence of myocardial injury,
orthostasis, postural orthostatic tachycardia syndrome (POTS), and
increased incidence of several cardiovascular diseases in observa-
tional studies, including cardiomyopathy and arrhythmias (Table 2).
Myocardial Injury and Myocarditis
Small observational studies have detected evidence of myo-
cardial injury or inflammation on CMR in patients recovered from
SARS-CoV-2 infection.37,39,49,54,55,63
Knight et al.55 evaluated a small cohort of 29 patients hospital-
ized for COVID-19 illness with unexplained myocardial injury, that
is, patients with no acute coronary syndrome or pulmonary embolism.
CMR was performed at a mean of 46 days after symptom onset or
27 days after discharge. Twenty of these patients had late gadolinium
enhancement (LGE) on CMR, 13 of which had a myocarditis-like pat-
tern.55 These findings suggested that, in patients with COVID-19 and
myocardial injury, a myocarditis-like scar may persist after discharge
and may be permanent. However, Knight et al.55 did not find associ-
ated myocardial edema suggesting ongoing inflammation.
In a larger study by Kotecha et al.,54 148 patients with severe
COVID-19 and myocardial injury underwent CMR at a mean of 68
days after discharge. In this cohort, 54% of the patients had LGE
and/or signs of ischemia on CMR. Myocarditis-like scar was pres-
ent in 26% of the patients, of which one-third had evidence of active
myocarditis.54 This high prevalence of myocarditis-like scar was con-
firmed in a larger study of 201 patients, of which 19% had a myocar-
ditis scar on CMR.39
Puntmann et al.38 evaluated 100 patients who recovered
from COVID-19 illness at a median of 71 days after diagnosis with
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high-sensitivity troponin T and CMR. High-sensitivity troponin T
was detectable in 71% of patients. In addition, 78% of patients had
abnormalities on CMR in the form of myocardial LGE (32%), peri-
cardial enhancement (22%), and raised myocardial native T1 (78%)
and T2 images (60%).38 Abnormal CMR findings were present inde-
pendent of illness severity or baseline comorbidities.38
There is scant literature on CMR findings in patients beyond
3 months of initial hospitalization.37,56 Myhre et al.37 evaluated the
results of CMR in 58 patients 6 months after discharge. Nine patients
had a minimal myocardial scar, 3 patients had left ventricular (LV)
dysfunction without a myocardial scar, and only 1 patient had a myo-
cardial scar associated with LV dysfunction.37
Based on the above studies, there is evidence to support the
persistence of myocardial injury, myocarditis, or pericarditis beyond
the acute infection in some patients. However, in patients in whom
myocardial injury persists, the anatomical extent and functional con-
sequence appear to be limited. In most of the studies, myocarditis-
like scar affected three or less anatomical segments37,54 and, in those
with more than three segments, it did not have associated LV dys-
function.39 Moreover, active myocarditis was limited to a minority
of patients (<10%).38,54 Although a study based on the VA popula-
tion showed that the risk of clinical myocarditis and pericarditis was
increased in patients who recovered from COVID-19 as compared to
contemporary controls, the absolute burden difference was consider-
ably low (1.23 per 1000 persons at 1 year),41 suggesting that clinical
features of these inflammatory syndromes are rare in the postacute
COVID period. Moreover, when comparing CMR abnormalities in
recovered COVID patients with controls, there was no difference in
the prevalence of inflammatory or ischemic scars, although the prev-
alence of LGE and raised myocardial T1 was higher in COVID-19
patients than in controls.49
Whether these imaging abnormalities can be a cause of post-
COVID symptoms, such as chest pain, is unclear. Dennis et al.39 cor-
related CMR findings with symptoms and found that only raised T1
myocardial affecting more than three anatomical segments was cor-
related with severe post-COVID symptoms. Further focus on the cor-
relation between imaging findings and symptoms would be essential
to better develop management strategies. In addition, most of these
studies evaluated patients before 12 weeks of discharge, limiting its
validity to extract conclusions for long COVID syndrome according
to most of the current definitions. Investigations at later stages of
recovery are needed to generate evidence specific to long COVID
syndrome and to establish whether these patterns of myocardial
injury may lead to an increased incidence of arrhythmias or heart
failure in the long term.
Left Ventricular Dysfunction
LV systolic dysfunction is not common during the acute phase
of infection. Data are controversial regarding the risk of LV dysfunc-
tion during the postinfectious period. Most studies based on imag-
ing techniques indicate that the incidence of LV dysfunction is not
increased after COVID-19.54,56–59 In several small studies of patients
recovered from COVID-19, including those with severe illness,
patients did not have LV dysfunction on echocardiogram 2–6 months
after discharge.56–59 Other imaging studies report a low prevalence
(<10%) of mostly mild LV dysfunction on follow-up echocardiog-
raphy or CMR.37,39,60–62 However, in most cases the prevalence of LV
dysfunction was not higher than in the control group,37,39 LV dysfunc-
tion was present since admission,61 or study design precludes from
knowing whether it was present at the time of admission.37,60 On the
other hand, diastolic dysfunction has been described with a preva-
lence of up to 60%.62 There is also limited evidence to determine
whether this was present at the time of admission or incident after
acute infection.
Lorente-Ros et al Cardiology in Review  •  Volume XXX, Number 00, xxx XXX

TABLE 2.  Cardiovascular Manifestations of Long COVID Syndrome.

Timing from
Cardiovascular Sequelae Objective Findings Prevalence Acute Infection References
Decreased exercise tolerance Abnormal 6-minute walk test 22%–29% 2–6 mo 18,48–50

Decreased peak oxygen consumption 55%

Myocardial injury LGE on CMR 16%–74% 1–6 mo 37–39,54–56

Myocarditis-like pattern on CMR, with or 19%–48%

without myocardial edema
Active myocarditis <10%
Pericardial enhancement 22%
Raised myocardial native T1 and T2 60%–78%
Left ventricular dysfunction Reduced LVEF measured in TTE or CMR 0%–<10% 2–6 mo 54,56–59
37,39,60–62
Diastolic dysfunction 60%
Right ventricular dysfunction Decreased RV longitudinal strain 0%–42% 2–6 mo 60,61,63
57,64
Decreased RV ejection fraction, stroke vol- 0%–16%
ume, TAPSE, fractional area shortening
Pulmonary hypertension Pulmonary hypertension estimated on TTE 0%–<10% 2–3 mo 57,61,62

Late thromboembolic events Venous thromboembolism <1% 1–4 mo 65–68

Arterial thromboembolism <1%

CMR indicates cardiac magnetic resonance; COVID, coronavirus disease 2019; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; RV, right ventricular;
TAPSE, tricuspid annular plane systolic excursion; TTE, transthoracic echocardiography.

In contrast to imaging studies, studies using electronic health
records have described a higher incidence of heart failure in patients
who recovered from COVID-19, as compared to controls. Xie et. al.41
reported an increased risk of both ischemic and nonischemic car-
diomyopathy in the VA cohort, albeit with a small absolute burden
difference of 2–4 per 1000 persons at 1 year.41 Al-Aly et al.35 also
described an increased incidence of heart failure in patients after
infection with SARS-CoV-2. In line with the results from the VA,
a descriptive cohort from Spain reported a 2% prevalence of heart
failure 1 year after discharge, although this was not compared to a
control group.47
Right Ventricular Dysfunction and Pulmonary
Hypertension
Right ventricular (RV) dysfunction affects between 14.5% and
33% of hospitalized patients during acute infection,44,69,70 and is an
independent risk factor for hospital mortality.69
Data are controversial regarding the persistence of RV dys-
function after acute illness and its functional implications. There
is some data indicative of persistent RV dysfunction after the acute
infection.60,61,63 In a study by Nuzzi et al.,57 overt RV dysfunction
based on fractional area shortening was not present. However, sub-
clinical RV dysfunction with decreased RV longitudinal strain was
found in 22 of 53 patients 74 days after discharge.57 Cassar et al.64
found that RV function 3 or 6 months after hospitalization was not
different in COVID-19 patients as compared to controls. Moreover,
there was an improvement in RV ejection fraction in CMR from 3 to
6 months of follow-up.64
Pulmonary hypertension can affect 12% of patients hospital-
ized with COVID-19.44 It is mechanistically possible that the micro-
angiopathy and micro-thrombotic burden from acute COVID-19
could lead to an increased prevalence of pulmonary hypertension
long term. However, evidence is lacking to support this.57,61 In the
study by Nuzzi et al.,57 none of the patients had pulmonary hyperten-
sion after recovery from acute infection.57 Sonnweber et al.62 reported
pulmonary hypertension in a minority of patients (10%) both 60 and
100 days from discharge.
Late Thromboembolic Events and Progression of
Atherosclerosis
SARS-CoV-2 is a well-established risk factor for thromboem-
bolism. Evidence is strong to suggest that the pro-thrombotic state
persists after discharge.71–73 Xie et al.41 found that patients who recov-
ered from COVID-19, compared to matched contemporary controls,
had an increased risk of pulmonary embolism and deep venous
thrombosis (DVT) at 1 year [HR (95% CI): 2.93 (2.73–3.15) and 2.09
(1.94–2.24), respectively]. This increased risk of thromboembolism
was consistent in another observational study.35 However, the abso-
lute risk of both DVT and pulmonary embolism remains low after
acute infection.65–68 In a study of 146 patients screened for thrombo-
embolic events 6 weeks after discharge, the incidence of DVT and
pulmonary embolism were both <1%.66
The risk of cerebrovascular events appears to be higher in
patients recovered from COVID-19, as compared to controls [HR:
1.52 (1.43–.62) for stroke and 1.49 (1.37–1.62) for TIA],41 with a
reported absolute incidence of stroke of up to 1.3%.47
Incident coronary artery disease has also been raised as a con-
cern in the post-infectious period of SARS-CoV-2. Patients recovered
from acute infection have a 1.6–1.7 times higher risk of new-onset
coronary artery disease or myocardial infarction compared to con-
trols.41 Other descriptive cohorts with no control group have found an
incidence of acute myocardial infarction of 1.5% in patients recov-
ered from COVID-19 at 1-year follow-up.47 It is possible that the pro-
gression of atherosclerosis is dependent on the severity of the initial
infection, and that the observed increased risk of stroke or coronary
artery disease only applies in patients who required hospitalization
during the acute infection.35
Arrhythmias
Patients who recovered from COVID-19 in large observational
studies had an increased risk of arrhythmias, compared to contem-
porary controls [HR: 1.69 (1.64–1.75)].41 This increased risk was
at the expense of atrial fibrillation, atrial flutter, sinus tachycardia,
sinus bradycardia, and ventricular arrhythmias. The highest burden
of arrhythmia was attributed to atrial fibrillation, with an absolute

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Cardiology in Review  •  Volume XXX, Number 00, xxx XXX Cardiovascular Manifestations of Long COVID Syndrome
burden difference of 20 per 1000 persons at 1 year, followed by sinus
tachycardia.41 This is consistent with the results from Zhou et al.,40
who report incident atrial fibrillation in 1 out of 97 patients at a
median of 11 days postdischarge.
Postural Orthostatic Tachycardia Síndrome
Despite palpitations being a common manifestation of long
COVID, its correlation with new onset tachyarrhythmias is often
lacking. Palpitations are often found in combination with lighthead-
edness and other symptoms of orthostatic intolerance, in which case
POTS should be suspected.
POTS is an increase in heart rate of >30 beats/minute within
10 minutes of upright posture associated with symptoms of orthosta-
sis, in the absence of orthostatic hypotension or alternative causes
of tachycardia.74 Although the diagnosis of POTS appears to have
increased after the pandemic, its incidence is difficult to estimate
from small case series, and the requirement of advanced autonomic
evaluation to confirm the diagnosis.75
PROPOSED PATHOPHYSIOLOGICAL MECHANISMS
Several mechanisms were proposed to explain cardiac injury
during the acute phase of SARS-CoV-2 infection. These include
direct viral invasion,76,77 cytokine release and dysregulated immune
response,78,79 endotheliopathy, and micro-thrombosis.80,81
The mechanisms that lead to cardiovascular manifestations of
long COVID syndrome are not well understood. Importantly, there is
a parallelism with incident metabolic and cardiovascular disease in
other postinfectious syndromes, such as after SARS-CoV infection
or bacterial pneumonia,82,83 which raises the possibility of a common
biological mechanism. Indeed, in a recent study, the increased risk
of cardiovascular disease after SARS-CoV-2 infection was similar
to that of patients hospitalized with other etiologies of pneumonia.45
Whether cardiovascular signs and symptoms of long COVID
are a consequence of the acute infection or a result of a new patho-
logical mechanism is unclear. It stands to reason that findings such as
ongoing myocardial injury or inflammation on CMR could be pres-
ent from the acute initial presentation. On the other hand, the cause
of subjective symptoms in the absence of abnormalities on cardiac
imaging, especially those related to autonomic dysfunction, are not
easily attributable to the persistence of complications from acute
infection.
Aside from the direct consequences of acute infection, such as
ongoing myocardial injury or complications of critical care illness,
the pathophysiology behind long COVID is proposed to be multifac-
torial. Autonomic dysfunction, chronic inflammation, and oxidative
stress perhaps sustained by the persistence of viral reservoirs, auto-
immunity, and sustained endotheliopathy and immunothrombosis are
some of the mechanisms thought to contribute.
Prolonged dysfunction of the sympathetic and parasympa-
thetic systems is thought to be one of the cornerstones of long COVID
syndrome. DePace and Colombo84 propose that the dysregulated
immune response that characterizes acute infection results in exces-
sive parasympathetic activation which, sustained over time, leads
to the excessive beta-adrenergic response, resulting in post-COVID
symptoms. DePace and Colombo85 also posit that, in response to the
acute viral infection, there are metabolic shifts in mitochondria such
as the downregulation of oxidative phosphorylation.86 These shifts
in metabolic pathways result in worsening oxidative stress, which
itself can also lead to alpha-adrenergic dysfunction and orthostatic
symptoms.84
Dysregulated inflammatory response and oxidative stress
are the hallmarks of acute SARS-CoV-2 infection and may also
have a role in incident metabolic and cardiovascular disease in the
postinfectious period, especially in relation to the progression of
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atherosclerosis. A prolonged proinflammatory response with cyto-
kine release can contribute to the destabilization of the atheroscle-
rotic plaque by facilitating macrophage migration to subintimal
low-density lipoprotein deposits, by thinning the fibrous cap, and by
increasing platelet activation.87 A possible component of autoimmu-
nity from cardiac molecular mimicry could also possibly contribute
to persistent symptoms, triggered by the persistence of viral genes,
as proposed by DePace and Colombo.84,88 However, further research
is needed to confirm this.
Thrombotic events, namely microthrombosis and immu-
nothrombosis in the pulmonary or systemic vasculature, can be
more easily explained as a direct result from the acute infection.
The prothrombotic state during acute infection is known to persist
in convalescent patients.71–73 D-dimer levels remain elevated in 25%
of patients up to 4 months after the acute infection.71 Fogarty et al.72
found increased thrombin-generating capacity in a small cohort of
50 patients 2 months after the initial infection. The endotheliopathy
that characterizes acute infection persists in patients recovered from
acute illness, who have higher von Willebrand factor antigen, von
Willebrand factor pro-peptide, factor VIII, and thrombomodulin,
as compared to controls.72 These markers of endothelial cell acti-
vation inversely correlated with the exercise capacity of patients,72
suggesting that persistent endotheliopathy may be a mechanism in
long COVID syndrome. The possibility that the micro-thrombotic
burden resulting from microangiopathy could lead to incident throm-
boembolic pulmonary hypertension or RV dysfunction needs to be
explored.
MANAGEMENT
The development of strategies for the management of car-
diovascular manifestations of long COVID syndrome is limited
by the disparities in reported incidence, the unclear biological
mechanisms, and the uncertain correlation between symptoms and
objective findings on cardiovascular testing. Nonetheless, scien-
tific societies have proposed several approaches based on available
evidence.8,89
Supportive Management
Lifestyle measures and supportive therapy with the purpose
of reducing systemic inflammation is the mainstay of therapy for all
manifestations of long COVID syndrome.8 These measures should be
focused on sleep hygiene, stress management, aerobic and anaerobic
exercise, and healthy dietary habits. Pulmonary rehabilitation pro-
grams in small studies have shown to improve 6-minute walk tests
and mental health symptoms in patients with decreased exercise
capacity after discharge from acute infection.90 As such, referral to
pulmonary rehabilitation should be considered in patients with poor
exercise tolerance not explained by cardiac pathology. Importantly,
another pillar of management of long COVID is a referral to other
specialty clinics, such as autonomic clinics, physical rehabilitation,
and psychotherapy, if indicated based on initial history and physical
examination.91
Cardiovascular Evaluation of High-Risk Individuals
Patients who had cardiovascular complications during the
acute infection and patients with new onset cardiopulmonary symp-
toms of long COVID should be evaluated by a cardiologist. The ini-
tial cardiology evaluation should include a comprehensive history,
a physical examination, and a 12-lead-electrocardiogram. Informa-
tion on the severity and complications of acute infection, results of
cardiopulmonary testing performed during admission, and treatment
received, with particular attention to antivirals, steroids, and throm-
boprophylaxis, should be collected during the initial visit. Additional
testing with high-sensitivity troponin, brain natriuretic peptide, lipid
Lorente-Ros et al Cardiology in Review  •  Volume XXX, Number 00, xxx XXX
panel, hemoglobin A1c, and transthoracic echocardiogram can also
be considered as part of the initial cardiology visit.89
Athletes should also be considered high-risk patients and
undergo a cardiology evaluation in their convalescent phase.
Although cardiac complications of SARS-CoV-2 acute infection
are infrequent in athletes,92 the risk of sudden cardiac death exists
even with subclinical myocarditis.93 As such, all competitive athletes
recovered from acute infection should undergo an initial evalua-
tion with a 12-lead electrocardiogram, high-sensitivity troponin,
and transthoracic echocardiogram. If there are clinical or imaging
concerns of myocarditis, stress cardiomyopathy, RV dysfunction, or
pericarditis, CMR is recommended as the next step in the evaluation
of these patients.94 Athletes in whom myocarditis is suspected, a 3–6
month rest period is recommended, given that even asymptomatic
myocarditis in these patients confers a risk of sudden cardiac death.
On the other hand, in competitive athletes with mild acute infection,
resolved symptoms, normal electrocardiogram and echocardiogram,
and negative troponin, graded return to exercise are considered
safe.94,95
Management of POTS and Autonomic Dysfunction
As exposed in prior sections of this review, orthostatic intol-
erance, including POTS syndrome, is a consequence of autonomic
dysfunction. The natural history and self-limiting capacity of ortho-
static syndromes after COVID-19 are unknown.74,96 Patients with sus-
pected orthostatic symptoms or those with suspicion of POTS should
be referred to autonomic clinics to confirm the diagnosis. Question-
naires such as the composite autonomic symptom scale-31 can vali-
date autonomic dysfunction in these patients.97
Therapeutic strategies for the management of dysautono-
mia include avoiding triggering factors (such as prolonged sitting),
expansion of plasma volume with salt and fluid intake, isometric
exercises, compression garments, and exercise training.84,98 Exer-
cise training should include both aerobic endurance training and
anaerobic resistance exercises, typically with weight lifting.99 The
individual patient’s peak exercise capacity should be determined
with standardized treadmill protocols before the start of training.99
Semi-recumbent exercises are preferred in the early stages of train-
ing to avoid triggering symptoms, gradually followed by upright
exercises.99
Particularly for POTS, exercise training as detailed above
remains the mainstay of therapy, as it has shown to improve or cure
the syndrome in most patients after 3 months.99,100 Depending on the
specific pathophysiology found on autonomic testing, drug therapies
may be considered in selected patients.98 Low-dose non-beta selec-
tive beta-blockers, specifically propranolol (10–20 mg daily), may
be considered in patients with confirmed hyperadrenergic POTS,
as it has shown to improve tachycardia and symptom burden.98,101
Phenobarbital and alpha-2 adrenergic drugs such as clonidine have
also proven to be useful in controlling symptoms in hyperadrener-
gic patients.98 Hypovolemic patients, in addition to increased salt
and fluid intake, may benefit from further plasma volume expansion
with fludrocortisone.98 Finally, in patients with neuropathic POTS
with underlying peripheral adrenergic failure, alpha-1 agonism with
midodrine can be used to improve symptoms.98
Management of Heart Failure and Myocarditis
Patients with heart failure during the post-COVID period
should be managed according to general guidelines.102,103 Similarly,
patients with suspected myopericarditis during the long COVID phase
should be treated according to current guidelines, given the lack of
data specific to myocarditis as part of long COVID syndrome.104,105
In patients with inflammatory myocarditis during the acute infection,
assessment of residual myocardial injury is of special importance,
as monomorphic ventricular arrhythmias have been described even
6  |  www.cardiologyinreview.com © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2023 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
in the convalescent phase of myocarditis, especially in patients with
heart failure, short duration of acute disease, and older age.106,107
Role of Prolonged Thromboprophylaxis
Evidence suggests that the prothrombotic state during COVID-
19 can persist in the postinfectious period for at least 2–4 months.71–73
Whether the risk of clinical thromboembolic events is increased after
discharge and whether postdischarge thromboprophylaxis can reduce
this risk remains controversial.
The absolute incidence of thromboembolic events after
SARS-CoV-2 infection is low (<1%).65–68 Moreover, some studies
have found no difference in the incidence of venous thromboembo-
lism (VTE) after COVID-19 compared to other acute medical ill-
nesses.65,67,68 A meta-analysis of four observational studies indicated
no association between postdischarge anticoagulation and incident
thromboembolic events in COVID-19 survivors.65
In contrast, a large observational study found that postdis-
charge anticoagulation in COVID-19 patients (either with prophy-
lactic or therapeutic dosing) was associated with a 46% reduction
in a composite outcome of venous/arterial thromboembolism and
all-cause mortality.108 In line with these results, a more recent meta-
analysis indicated a 48% reduction in thromboembolic events with
post-discharge thromboprophylaxis in patients deemed at high risk
of thromboembolism.109 This meta-analysis included the Medically
Ill Hospitalized Patients for COVID-19 Thrombosis Extended Pro-
phylaxis With Rivaroxaban Therapy randomized controlled clinical
trial, which included 320 patients at increased risk for VTE (Inter-
national Medical Prevention Registry on Venous Thromboembolism
VTE score of ≥4 or 2–3 with a D-dimer >500 ng/mL). The Medi-
cally Ill Hospitalized Patients for COVID-19 Thrombosis Extended
Prophylaxis With Rivaroxaban Therapy trial investigators found that
rivaroxaban 10 mg/day for 35 days reduced the risk of the composite
primary endpoint (venous/arterial thromboembolism and cardiovas-
cular death) by 67%, as compared to no anticoagulation.110
Given the inconsistent results of observational studies and
meta-analyses, the expert guideline recommendations for postdis-
charge anticoagulation after COVID-19 are conflicting, with most
of the recommendations based on the low or moderate quality of
evidence.111 The National Institutes of Health currently recommends
against routine anticoagulation after hospital discharge, except for
patients who have another indication for anticoagulation or are
participating in a clinical trial.112 The National Institutes of Health
do not recommend for or against postdischarge anticoagulation in
patients at high risk for VTE and low risk of bleeding, on the basis
of insufficient evidence.112 Other COVID-19 guidelines have recom-
mended postdischarge anticoagulation in patients deemed at high
risk of thromboembolism. Specifically, The Scientific and Standard-
ization Committee of the International Society on Thrombosis and
Haemostasis recommends either low molecular weight heparin or
a direct oral anticoagulant for at least 2 weeks and up to 6 weeks
postdischarge in patients with VTE risk factors who are at low risk
for bleeding.113 The British Thoracic Society suggests considering
prophylactic thromboprophylaxis for up to 4 weeks in patients who
are at high risk of VTE and low risk of bleeding.114 What seems clear
is that decisions on postdischarge anticoagulation should be indi-
vidualized to each patient’s risk of thromboembolism and bleeding,
and that participation of eligible patients in clinical trials should be
encouraged.112
Role of Vaccination
The role of vaccination in preventing the development of long
COVID is based on the reduction of progression to severe disease,
which reduces the risk of long COVID. This protective role of vac-
cination for long COVID has been discussed in more detail in a
prior section of this review. In addition, in previously unvaccinated
Cardiology in Review  •  Volume XXX, Number 00, xxx XXX Cardiovascular Manifestations of Long COVID Syndrome
patients suffering from symptoms of long COVID, vaccination with
messenger RNA vaccines has been proposed to reduce symptoms in
up to 58% of the patients.115 This evidence is however, not specific to
cardiovascular symptoms, has considerable variability in individual
response and is subject to bias as it is based on patient surveys.
FUTURE OUTLOOK
It is clear that both incident and persistent cardiovascular man-
ifestations after COVID-19 are responsible for a significant symptom
burden in convalescent patients. A better understanding of cardiac
involvement in long COVID is needed to establish appropriate thera-
peutic strategies.
First, the correlation between symptoms and objective find-
ings on cardiac imaging needs to be clarified. Future study designs
should focus on the clinical implications of persistent signs of myo-
cardial injury and whether cardiopulmonary symptoms are better
explained by cardiac pathology, abnormalities in respiratory physi-
ology, lung fibrosis, autonomic dysfunction, or merely decondition-
ing. Research providing insight on the pathophysiology behind these
symptoms would facilitate to establish this correlation.
Second, the natural history of cardiovascular symptoms as part
of long COVID syndrome is not clear. Whether these symptoms are
transitory or whether they may persist for years as in other corona-
virus infections would impact the required response from healthcare
systems and allow physicians to provide patients with information
regarding their prognosis.
Third, the development of management strategies is of immi-
nent importance. Various clinical trials are ongoing with the aim
to establish the benefit of rehabilitation, immunosuppressive thera-
pies (steroids), anti-inflammatory therapies (statins, aspirin, and
colchicine), thromboprophylaxis, and antifibrotic therapies in long
COVID syndrome (As examples: NCT04801940, NCT04988282,
NCT04988282, and NCT04628039). These studies mostly evaluate
outcomes such as fatigue, neurocognitive improvement, and pul-
monary recovery. As such, they are not specifically focused on the
treatment of cardiac pathology. In the absence of evidence specific to
cardiac sequelae after COVID-19, cardiovascular specialists should
evaluate and treat patients at high risk of persistent or incident cardio-
vascular disease according to current expert guidelines. Importantly,
healthcare systems should focus on establishing effective ways of
referral to both cardiac specialists and autonomic clinics to facilitate
the diagnosis and treatment of patients with long COVID syndrome
and be prepared for what appears to be an increased incidence of
cardiovascular disease in COVID-19 survivors.
CONCLUSIONS
Long COVID syndrome affects up to one in four patients after
acute infection. Cardiovascular manifestations of long COVID syn-
drome are common and mostly present in the form of dyspnea, chest
pain, palpitations, and orthostasis. Evidence suggests that myocar-
dial injury and inflammation can persist in the postinfectious period.
Moreover, some observational studies indicate an increased incidence
of cardiovascular disease in COVID-19 survivors. The pathophysiol-
ogy behind these manifestations is unclear but systemic inflamma-
tion appears to play an important role. Future research should focus
on clarifying the natural history of long COVID syndrome, as well as
establishing effective management strategies focused on both reduc-
ing symptom burden and facing an increased incidence of cardiovas-
cular disease after the SARS-CoV-2 pandemic.
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