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Department of Medicine and Joint Department of Medical Imaging, Toronto Hospital Research Institute and Schroeder Arthritis Institute, University Health NetworkDepartment of Medicine, University of Toronto
Department of Medicine and Joint Department of Medical Imaging, Toronto Hospital Research Institute and Schroeder Arthritis Institute, University Health NetworkDepartment of Medicine, University of Toronto
Department of Medicine and Joint Department of Medical Imaging, Toronto Hospital Research Institute and Schroeder Arthritis Institute, University Health NetworkDepartment of Medicine, University of Toronto
Department of Medicine and Joint Department of Medical Imaging, Toronto Hospital Research Institute and Schroeder Arthritis Institute, University Health NetworkDepartment of Medicine, University of Toronto
Department of Medicine and Joint Department of Medical Imaging, Toronto Hospital Research Institute and Schroeder Arthritis Institute, University Health NetworkDepartment of Medicine, University of Toronto
Department of Medicine and Joint Department of Medical Imaging, Toronto Hospital Research Institute and Schroeder Arthritis Institute, University Health NetworkDepartment of Medicine, University of Toronto
Department of Medicine and Joint Department of Medical Imaging, Toronto Hospital Research Institute and Schroeder Arthritis Institute, University Health NetworkDepartment of Medicine, University of Toronto
Department of Medicine and Joint Department of Medical Imaging, Toronto Hospital Research Institute and Schroeder Arthritis Institute, University Health NetworkDepartment of Medicine, University of Toronto
Statistics Canada estimates that approximately 1.4 million Canadians suffer from long COVID. While cardiovascular changes during acute SARS-CoV-2 infection are well documented, long-term cardiovascular sequelae are less understood. In this review, we sought to characterize adult cardiovascular outcomes seen in the months following acute COVID-19 illness. Our search identified reports of outcomes including cardiac dysautonomia, myocarditis, ischemic injuries, and ventricular dysfunction. Even in patients without overt cardiac outcomes, subclinical changes have been observed. Cardiovascular sequelae following SARS-CoV-2 infection can stem from exacerbation of pre-existing conditions, ongoing inflammation, or as a result of damage occurring during acute infection. For example, myocardial fibrosis has been reported months after hospital admission for COVID-19 illness, and may be a consequence of myocarditis and myocardial injury during acute disease. In turn, myocardial fibrosis can contribute to further outcomes including dysrhythmias and heart failure. Severity of acute infection may be a risk factor for long-term cardiovascular consequences, however, cardiovascular changes have also been reported in young, healthy individuals who had asymptomatic or mild acute disease. Although evolving evidence suggests that prior SARS-CoV-2 infection may be a risk factor for cardiovascular disease, there is heterogeneity in existing evidence, and some studies are marred by both measured and unmeasured confounders. Many investigations have also been limited by relatively short follow up. Future studies should focus on longer term outcomes (beyond 1 year) and identifying the prevalence of outcomes in different populations based on acute and long COVID disease severity.
Introduction
It is well-documented that multi-organ symptoms of SARS-CoV-2 infection can persist after recovery from acute illness. The resulting post-COVID condition, often referred to as long COVID, has emerged as a “post-pandemic pandemic”. As of August 2022, it is estimated that nearly 15% of COVID-19 survivors, or approximately 1.4 million adult Canadians, are continuing to experience post-COVID symptoms at least 3 months after a confirmed or suspected infection.
Statistics Canada. Long-Term Symptoms in Canadian Adults Who Tested Positive for COVID-19 or Suspected an Infection, January 2020 to August 2022.; 2022.
Several definitions for post-acute sequelae of COVID-19 have been suggested, with long COVID often used as a general term. According to the World Health Organization (WHO), post-COVID condition is defined as the presence of post-COVID symptoms that persist past 3 months, last for at least 2 months, and cannot be explained by an alternative diagnosis.
The National Institute for Health and Care Excellence (NICE) in the UK has divided the post-acute COVID-19 period into ongoing symptomatic COVID-19 at 4-12 weeks, and post-COVID syndrome (>12 weeks).
Post-COVID Conditions: Information for Healthcare Providers. Accessed December 26, 2022. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html
Despite slight variation in terminology and definition, all groups recognize that common long COVID symptoms include fatigue, shortness of breath, and cognitive dysfunction. Long COVID can be debilitating, leading to exercise intolerance and inability to return to work,
To date, there has been no established link between SARS-CoV-2 infection and major long-term cardiovascular risk. However, some epidemiologic evidence suggests that COVID-19 may be associated with long-term increased risk of cardiovascular outcomes.
The Canadian Cardiovascular Society (CCS) Rapid Response team suggests consultation with a cardiologist for patients who experience persistent chest pain, shortness of breath, frequent palpitations, or postural lightheadedness >4 weeks after COVID-19 diagnosis.
Since these symptoms are non-specific and may be related to other conditions, investigations are encouraged to differentiate between cardiac and other etiologies. The incidence and nature of the long-term cardiovascular consequences of COVID-19 have yet to be fully characterized.
In this review, we sought to summarize existing evidence on cardiovascular sequelae following SARS-CoV-2 infection (Figure 1). Specifically, we focused on outcomes occurring longer than one month after acute COVID-19 illness. We also considered a breadth of possible outcomes, even those that are thought to be less often associated with viral respiratory infections. A summary of papers that fulfill the WHO definition of long COVID (symptoms persisting for ≥3 months) were included in Table 1.
Figure 1Long-term cardiovascular complications of COVID-19 illness., LV = Left Ventricle, LV = Right Ventricle, POTS = Postural Orthostatic Tachycardia Syndrome
N=204 post-COVID N=204 controls Mean (SD) age: 58.5 (13.6) years 56% male
Hospitalized and ICU
Cardiac function assessed at 3 to 4 months after hospital discharge for acute COVID illness
•Arrhythmias found in 27% of patients, of which 18% were premature ventricular contractions •Post-COVID patients had worse right ventricle free longitudinal strain, lower tricuspid annular plane systolic excursion, and cardiac index compared to controls
N=10 underwent CMR Mean (SD) age: 44.6 (8.0) years 20% male Patients evaluated in long-COVID unit
Mild to moderate severity
Stress perfusion CMR at mean of 8.2 months (IQR: 3.2-11.4) after infection
•27% of patients evaluated in long-COVID unit had chest pain •Of 10 patients who underwent CMR, 5 (50%) showed significant circumferential subendocardial perfusion
Ischemic myocardial injuries and microvascular disease
N=153 Median (range) age: 57 (49-66) 52% male Patients considered if received transthoracic echocardiogram during initial COVID-related hospitalization
Hospitalized (32% ICU)
Mean (SD) of 129 (60) days after acute COVID-19 illness
•Patients with hyperdynamic LVEF at baseline showed reduced LVEF at follow up (-8.8%, p<0.001) •Patients with abnormally low LVEF values on baseline showed significant increase by follow up (+6.7%, p=0.02). •Patients with normal LVLS at baseline showed significant worsening at follow-up (1.2%, p=0.006) •Patients with impaired LVLS at baseline showed significant improvement at follow up (-2.2%, p<0.001) •Patients with abnormal RVLS at baseline had significant improvement by follow-up (p=0.004)
Left ventricular (LV) dysfunction Right ventricular (RV) dysfunction
Echocardiography evaluation 6 ± 1 months post-hospitalization for SARS-CoV-2 infection
•E/e′ ratio after low-level exercise was increased in patients who experienced myocardial injury during acute COVID-19 illness compared to those without myocardial injury during acute illness (10.1 ± 4.3 vs. 7.3 ± 11.5, P = 0.01) •Diastolic abnormalities seen without systolic involvement
Combined cardiac fluorodeoxyglucose-positron emission tomography/magnetic resonance imaging assessment of myocardial injury in patients who recently recovered from COVID-19.
N=47 Mean (SD) age: 43 (13) years 49% male Patients invited by mail after testing positive for COVID-19 at center
85% recovered at home
Baseline PET at mean (SD) of 67 (16) days after COVID-19 diagnosis Follow-up PET 52 (17) days later
At baseline PET, 17% (n=8) patients had focal FDG uptake, indicative of myocardial inflammation •At follow-up, these patients showed improvements in PET/MRI and blood biomarkers
N=13 with cardiac injury during hospitalization N=14 controls without cardiac injury during hospitalization Median (range) age: 63 (58-70) years 29.6% male
Hospitalized
Up to 6 months after hospital discharge
Positive LGE from CMR in 29.6% of all patients
Ischemic myocardial injuries and microvascular disease
N=201 (36 controls) Mean (range) age: 45 (21-71) years 29% male Recruited participants with persistent post-COVID symptoms
81% non-hospitalized
Median 141 days (IQR 110-162) after initial COVID-19 symptoms
•Myocarditis seen in 19% of post-COVID patients (compared to 5.6% of healthy controls [note, p=0.053]) •Report of severe post-COVID condition was associated with higher likelihood of myocarditis compared to moderate post-COVID condition (25.0% vs 11.7%, p=0.027) •LVEF and LV end diastolic volume not significantly different between post-COVID patients and healthy controls •Systolic dysfunction was observed in 9% of post-COVID patients
N=102 Median age: 52 years 59% male Participants with confirmed SARS-CoV-2 infection were recruited from community
19% hospitalized
Echocardiogram at a median of 7.2 months (IQR 4.1-9.1) after SARS-CoV-2 infection
N=4 patients (9%) with cardiopulmonary symptoms (dyspnea, chest pain, palpitations) had evidence of pericardial effusion, compared to 0 patients without symptoms (note, p=0.11)
N= 443 post-COVID cases N = 1328 matched controls Median (IQR) age of cases: 55 (51,60) years 47.4% male Post-COVID patients were invited after identification in clinical information system
Mild to moderate severity (non-hospitalized)
Median 9.6 months after a positive SARS-CoV-2 test
Compared to controls, post-COVID patients showed: •Longer QT intervals but not other ECG abnormalities •Trend of increased focal myocardial fibrosis, but comparable diffuse myocardial fibrosis •Lower LV and RV function higher hs-Trp, NT-proBNP
Arrhythmias Myocardial fibrosis Left ventricular (LV) dysfunction
N=105 post-COVID cases N=105 controls Mean (SD) age: 43.5 (12.5) years 60.9% male Previously treated COVID-19 outpatients
Mild (outpatient, non-hospitalized, with fever, muscle and/or joint pain, cough, sore throat, no respiratory distress)
Echocardiography at 3 months after COVID-19 diagnosis
Decrease in RV-GLS, RV-FWLS, and TAPSE negatively correlated with levels of C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), d-dimer, ferritin, and platelet to lymphocyte (PLR) during acute phase of SARS-CoV-2 infection
N=74 seropositive N=75 matched controls Median (range) age: 37 (18-63) years 42% male Participants recruited from prospective study on healthcare workers
Mild (Ranging from asymptomatic to symptoms of fever, dry cough, anosmia, ageusia, dysgeusia)
Cardiovascular phenotyping at 6 months 9 days (IQR: 5 months 26 days – 6 months 20 days) after SARS-CoV-2 infection
No difference between seropositive patients and controls in: •Late gadolinium enhancement •T1 and T2 signals •Myocarditis-like scarring
Cardiovascular magnetic resonance evaluation of soldiers after recovery from symptomatic SARS-CoV-2 infection: a case–control study of cardiovascular post-acute sequelae of SARS-CoV-2 infection (CV PASC).
N=50 cases with cardiopulmonary symptoms N=50 controls Median (IQR) age of cases: 26.5 (23-31) years 98% male Soldiers referred for CMR for cardiopulmonary symptoms after COVID-19 (e.g., abnormal ECG, chest pain)
4% mild 86% moderate 10% hospitalized
Initial CMR conducted at median of 71 days post SARS-CoV-2 detection Myocarditis cases from initial CMR underwent 1st follow-up CMR at range of 82 – 122 days, and 2nd follow-up CMR at range of 119 – 271 days
At first CMR: •11 cases (22%) had myocardial LGE •4 cases (8%) diagnosed with myocarditis At follow-up CMR: •2/4 myocarditis cases had complete resolution (119 and 245 days post-SARS-CoV-2 detection)
N= 20 70% female Median (range) age: 40 (25-65 years) Chart Review of patients referred to dysautonomia clinic (had no prior orthostatic intolerance)
Mild or non-hospitalized
Residual autonomic symptoms 6-8 months after SARS-CoV-2 infection
•85% had residual self-reported autonomic symptoms 6-8 months after COVID-19 infection •12 (60%) unable to return to work due to symptoms •15 (75%) had POTS diagnosed after COVID-19 infection
We conducted our literature search in Ovid MEDLINE with a focus on adult populations. In order to include the broad use of the term ‘long COVID’, we included studies focusing on outcomes occurring at 4 weeks or longer post-infection. Please see Supplemental Material S1 for details on our search strategy. This review first examines evidence on clinical cardiovascular outcomes observed after acute COVID-19 infection followed by potential mechanisms.
Myocarditis and Pericarditis
Myocarditis
Myocarditis has been observed in the acute phases of COVID-19 illness
, raising concerns about long-term myocardial injury. Myocarditis, myocardial inflammation and myocardial edema have previously been linked to viral infections, but most patients recover from myocardial inflammation within weeks of acute infection and don’t suffer long-term consequences.
Similarly, myocarditis has been observed in the weeks following acute SARS-CoV-2 infection, with a limited number of studies focusing on longer-term outcomes.
Kotecha et al. studied 148 patients who presented with elevated troponin levels during hospitalization for acute SARS-CoV-2 infection. At a median of 68 days (IQR 39-103) following COVID-19 diagnosis, there was a 27% rate of myocarditis-pattern late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (MRI) consistent with myocarditis. One third of the cases with myocarditis-pattern LGE showed signs of ongoing active myocardial inflammation. However, regional wall motion and biventricular function remained normal.
In a German study of 100 patients (33% requiring hospitalization for acute COVID-19 illness), cardiac MRI performed at a median of 71 days (IQR 64-92) after COVID-19 diagnosis revealed abnormal findings in 78% of patients, including ongoing myocardial inflammation in 60% of patients. LGE was seen in 32% of patients and myocardial native T1 and T2 signals were increased in 73% and 60% of patients, respectively. Findings were independent of pre-existing conditions, disease severity, and overall course of the acute illness.
Post‐COVID-19 myocarditis was also investigated in a case series of 14 patients hospitalized for new cardiac symptoms 1-5 months after acute COVID-19 illness. These patients had no previous history of myocarditis, valvular heart diseases, hypertensive heart disease, nor evidence of coronary artery stenoses over 50%. Myocarditis in these patients was diagnosed by a myocardial biopsy conducted during hospitalization on average at 5.5 months after SARS-CoV-2 infection. Histological findings of lymphocytic myocarditis were observed in 12 patients, eosinophilic myocarditis in 2 patients, and endocarditis in 3 patients. Similar to previously cited studies, these results show that SARS‐CoV‐2 infection can lead to subacute/chronic myocarditis.
In some cases, post-COVID-19 myocardial inflammation can remain subclinical. From a study of 16 patients hospitalized for acute SARS-CoV-2 infection with raised troponin levels or ECG abnormalities, 56% showed cardiac MRI abnormalities at a median 56 days post-acute illness, but only three patients (19%) fulfilled Lake Louise Criteria for myocardial inflammation.
Of these three patients, two were asymptomatic, and only one showed elevated troponin levels at follow-up. Cardiac MRIs can help with myocarditis identification and risk-stratification in patients who show initial elevated cardiac biomarkers or ECG abnormalities in the acute phase.
There is some evidence of myocarditis in otherwise low-risk individuals, particularly in the early convalescent period following mild acute disease. For example, in an investigation of 26 college athletes who experienced mild or asymptomatic acute COVID-19 illness, cardiac MRI revealed features of myocarditis in 15% of participants at 11-53 days post-infection.
In another study of 201 long COVID patients with a low rate of acute COVID-19 hospitalization and comorbidities, there was a 19% rate of myocarditis at a median of 141 days (IQR 110–162) following infection. Yet, the rate did not reach statistical significance when compared to healthy controls (5.6% [p=0.053]). This study identified myocarditis as the presence of three or more segments with high T1 signals. Severe long COVID (defined as persistent breathlessness, Dyspnoea-12 survey score ≥10, or EQ-5D-5L report of moderate or more severe problems with usual activities) was also associated with a significantly higher likelihood of myocarditis compared to moderate disease (p=0.027).
However, in a long-term study of 149 healthcare workers at 6 months post-infection, cardiac MRI revealed no difference in myocarditis-like scarring between patients with prior mild SARS-CoV-2 infection and seronegative controls.
In one study, 47 primarily non-hospitalized COVID-19 patients were tested using cardiac focal fluorodeoxyglucose (FDG) uptake on PET at a mean of 67 ± 16 days after COVID-19 diagnosis.
Combined cardiac fluorodeoxyglucose-positron emission tomography/magnetic resonance imaging assessment of myocardial injury in patients who recently recovered from COVID-19.
Results consistent with myocardial inflammation were seen in 17% (n=8) of patients. Although evidence of inflammation was seen from cardiac MRI and blood biomarkers in most of these patients, only three individuals met Lake Louise Criteria for myocarditis. As measured during a later follow-up, PET/MRI and inflammatory blood markers resolved or improved after a mean (SD) of 52 (17) days post-baseline. Clark et al. also observed that in cases of myocarditis diagnosed with modified Lake Louise Criteria at a median of 71 days post SARS-CoV-2 detection, subsequent follow-up showed recovery and gradual LGE resolution in two of four patients; one at 119 days and one at 245 days.
Cardiovascular magnetic resonance evaluation of soldiers after recovery from symptomatic SARS-CoV-2 infection: a case–control study of cardiovascular post-acute sequelae of SARS-CoV-2 infection (CV PASC).
This resolution in LGE suggests that cardiac inflammation present after acute COVID-19 illness may improve over time.
Although several studies have investigated myocarditis-like changes on cardiac MRI after resolution of acute SARS-CoV-2 infection, few studies have employed the Lake Louise Criteria for diagnosis. Thus, observed rates of myocarditis in patients with long COVID should be interpreted with caution. Indeed, in studies that have referred to the guidelines, few cases fulfill the criteria even when some cardiac changes are present. In cases where Lake Louise Criteria is not referenced, the association between myocarditis-like changes and cardiac outcomes is unclear. Specifically, in studies reported in this section that primarily did not reference Lake Louise Criteria, resolution of myocarditis or no mortality was reported. Granted, the follow up periods in these studies were within 1 year. Despite no significant reductions in cardiac function in post-COVID-19 myocarditis, minor reductions in RVEF have been observed in at least 3 studies.
Cardiovascular magnetic resonance evaluation of soldiers after recovery from symptomatic SARS-CoV-2 infection: a case–control study of cardiovascular post-acute sequelae of SARS-CoV-2 infection (CV PASC).
Cardiovascular magnetic resonance evaluation of soldiers after recovery from symptomatic SARS-CoV-2 infection: a case–control study of cardiovascular post-acute sequelae of SARS-CoV-2 infection (CV PASC).
Isolated pericardial involvement, including pericarditis and pericardial effusion, has not been commonly reported in studies of long-term cardiovascular outcomes after acute COVID-19 illness. Durstenfeld et al. showed that 9% of patients with cardiopulmonary symptoms including dyspnea, chest pain, and palpitation 7.2 months after initial SARS-CoV-2 infection had trace pericardial effusion measured through echocardiography. None of these patients had comorbidities that would increase the risk of pericardial effusion development. However, no echocardiographic signs of significant hemodynamic changes were observed among these cases.
Daher A, Balfanz P, Cornelissen C, et al. Follow up of patients with severe coronavirus disease 2019 (COVID-19): Pulmonary and extrapulmonary disease sequelae. Respir Med. 174:106197. doi:10.1016/j.rmed.2020.106197
Tachycardia is one of the more commonly observed cardiovascular symptoms after acute COVID-19 illness. Indeed, Post-COVID Tachycardia Syndrome has been proposed as a sub-syndrome of long COVID, and may present as both Inappropriate Sinus Tachycardia (IST) and Postural Orthostatic Tachycardia Syndrome (POTS) seen after acute illness.
Decreased heart rate variability (HRV) parameters were seen in patients with IST. Decreased HRV may be associated with other long-term cardiovascular complications including coronary insufficiency and coronary heart disease.
IST and decreased HRV can be attributed to an autonomic nervous system imbalance and decreased parasympathetic nervous system activity, compensated by increased sympathetic nervous system activation.
In a similar study assessing long COVID patients using 24-hour Holter monitoring, the LF/HF (low frequency to high frequency) ratio, which reflects the sympathovagal balance, was higher in COVID-19 patients with decreased HRV and therefore higher sympathetic activity due to dysautonomia.
Multiple studies have suggested that prevalence of both sinus tachycardia and bradycardia are increased after acute COVID-19 illness. These changes can be transient or sustained,
with resolution seen in long-term follow up. For example, a study from Hong Kong demonstrated significant bradycardia (heart rate below 50 bpm) in 7.2% of 97 patients at 1-4 weeks post-discharge, but changes resolved several weeks later.
Evidence suggests that even healthy patients with relatively mild or asymptomatic infection may develop POTS months after COVID-19 diagnosis. In a case series of 20 patients who presented with autonomic symptoms after acute COVID-19 illness, 15 were diagnosed with POTS.
At 6-8 months following SARS-CoV-2 infection, 85% of all patients self-reported residual autonomic symptoms such as dizziness, syncope and palpitations, with 60% unable to return to work. Some long COVID patients also present with POTS alongside orthostatic intolerance, and experience overlapping symptoms such as tachycardia, dizziness and cognitive dysfunction.
This in turn may disrupt normal blood pressure regulation and lead to the symptoms associated with these syndromes.
Arrhythmias
Patients from a wide range of demographics and severity of acute COVID-19 disease have shown increased incidence of arrhythmias in the months following infection. A database study of over 150,000 COVID-19 patients found that post-infection patients had a higher incidence of dysrhythmias 12 months after a positive COVID-19 test than healthy controls. Increased risks included sinus tachycardia (HR = 1.84 [1.74, 1.95]), atrial fibrillation (HR = 1.71 [1.64, 1.79]), atrial flutter (HR = 1.80 [1.66, 1.96]), ventricular arrhythmias (HR = 1.84 [1.72, 1.98]), and sinus bradycardia (HR = 1.53 [1.45, 1.62]).
In a study of 204 patients hospitalized for severe acute COVID-19 illness, arrhythmias were found in 27% of patients at 3-4 months post discharge, with premature ventricular contractions (18%) being the most common.
While patients with severe acute infection may be predisposed to a risk of arrhythmias, reports have shown that relatively mild acute COVID-19 disease can also be associated with rate and rhythm abnormalities after acute COVID-19 illness.
, A screening of 97 patients after non-severe acute COVID-19 illness found rhythm abnormalities in one third of patients at 3-4 months post infection, including sinus bradycardia (29.9%), and new onset atrial fibrillation (1%).
An investigation of 443 primarily non-hospitalized patients showed longer corrected QT intervals but no difference in other rhythm abnormalities compared to controls at a median of 9.6 months after acute illness.
Promisingly, risk of post-COVID arrhythmias decreases over time after initial infection. One matched cohort study of over 400,000 COVID-19 patients without cardiovascular diseases found increased incidence of atrial arrhythmias in the acute phase (1-4 weeks) following infection (RR 6.44, 4.17 to 9.96), but incidence decreased between 5 and 12 weeks (RR 1.58, 1.10 to 2.27), and further by 13 weeks and onwards (RR 0.85, 0.68 to 1.05).
This suggests that patients are most at risk of developing arrhythmias shortly following SARS-CoV-2 infection.
With regards to mechanisms of action, myocardial fibrosis and resultant cardiomyopathy from infection have been suggested to lead to re-entrant arrhythmias. It is also suggested that cytokine release (Interleukin-6 [IL-6], Interleukin-1 [IL-1], Tumor Necrosis Factor α [TNFα]) can increase catecholaminergic states. This may worsen existing arrhythmias by changing cardiomyocyte ion channel expression and thus extending ventricular action potentials.
Although post-COVID-19 chest pain may be explained in part by non-cardiac causes including anxiety, musculoskeletal, and pulmonary factors, myocardial injuries may also be present. While myocardial infarction has been observed in the acute phase of COVID-19 illness,
Possible mechanisms for myocardial injury and microvascular dysfunction in COVID-19 illness include direct damage by SARS-COV-2 on the myocardium, general inflammation and cytokine storm, and a hypercoagulable state.
The hypercoagulable state induced by SARS-CoV-2 promotes endothelial damage and plaque rupture, increasing the risk of myocardial infarction and coronary thrombosis.
Predictors of myocardial injury following SARS-CoV-2 infection have been examined. Troponin T level during acute illness has been shown to be a predictor for recovery and long-term cardiac sequelae in patients who had an episode of acute cardiac injury during hospitalization for acute COVID-19.
Patients with COVID-19 who experience a myocardial infarction have complex coronary morphology and high in-hospital mortality: Primary results of a nationwide angiographic study.
This association may also be relevant in the context of long COVID.
Indeed, cardiac ischemic findings have been observed after hospitalization for severe COVID-19 illness. In a study of patients admitted to ICU who received mechanical ventilation during their acute COVID-19 illness, 19% had newly diagnosed coronary artery disease 6 months after ICU admission.
In another study of patients who were hospitalized with severe SARS-CoV-2 infection and presented with elevated Troponin levels on admission, 26% showed ischemic pattern findings on a follow-up cardiac MRI 2 months after hospitalization.
Of these patients, 95% had at least one cardiovascular risk factor, but 66% had no history of ischemic heart disease and this was their first presentation of coronary artery disease. Nevertheless, as most patients had risk factors, it is possible that tachycardia, fever, and hypoxia during acute COVID-19 illness unmasked pre-existing, previously compensated, coronary artery disease and resulted in ischemic injuries.
Other studies have not found overt ischemic changes after acute COVID-19 illness. For example, Ródenas-Alesina and colleagues investigated myocardial infarction and mortality outcomes in COVID-19 patients with no previous cardiovascular disease at 7 months post hospitalization.
The authors found no difference in outcomes between those who were initially admitted with elevated high-sensitivity Troponin (hs-TnI >45 ng/L) compared to those without.
However, even when overt ischemic changes are not observed, other underlying changes may be present. One study examined patients with no history of cardiovascular disease who experienced chest pain and were referred to a long COVID outpatient clinic.
Despite the absence of any ischemic patterns and myocardial T1 and T2 mapping changes, adenosine stress perfusion cardiac MRI showed significant circumferential subendocardial perfusion defect in 50% of cases over 8 months after SARS-CoV-2 infection. This is highly suggestive of microvascular dysfunction. Similarly, Wu et al investigated patients without a history of coronary heart disease who suffered from cardiac injury during the acute phase of COVID-19 illness.
Patients returned to normal cardiac function within a 6-month follow-up. However, cardiac MRI revealed significantly higher proportion in positive LGE in the cardiac injury group compared to controls, suggestive of myocardial fibrosis. Fibrosis after SARS-CoV-2 infection can result from myocardial damage during acute illness,
Severe acute respiratory syndrome-associated coronavirus nucleocapsid protein interacts with Smad3 and modulates transforming growth factor-beta signaling.
Acute myocardial injury, including ischemic myocardial involvement and myocarditis, can lead to myocardial fibrosis following recovery from acute SARS-CoV-2 infection.
Indeed, several studies have reported that approximately 20-30% of their patient populations experience myocardial fibrosis after recovery from acute SARS-CoV-2 infection.
, For example, in a prospective study of 159 patients hospitalized with COVID-19, Morrow et al. found that one in five patients had evidence of myocardial fibrosis 28-60 days post-discharge.
Interestingly, a third study found a trend of increased focal myocardial fibrosis among primarily non-hospitalized COVID-19 survivors, yet findings of diffuse myocardial fibrosis were comparable to the control group.
Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks.
Among over 150,000 individuals, the risk of both ischemic and non-ischemic cardiomyopathy was higher in SARS-CoV-2 positive individuals (30 days after positive test) than in non-infected controls (HR = 1.75 [1.44, 2.13] and 1.62 [1.52, 1.73], respectively.
A similar conclusion was reached in a study of over 690,000 non-vaccinated individuals who tested positive for COVID-19, with an increased risk of ischemic cardiomyopathy (HR [95% CI] = 2.81 [2.48-3.19]) 1 to 12 months after a positive COVID-19 test.
Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks.
Ischemic cardiomyopathy was ranked within the top two cardiovascular risks (HR [95% CI] = 2.81 (2.48-3.19) following COVID-19 illness for all age categories, and was more pronounced in females.
Long-term cardiovascular outcomes in COVID-19 survivors among non-vaccinated population: A retrospective cohort study from the TriNetX US collaborative networks.
It is difficult to disentangle the impact of direct viral infection from pandemic-related stress when examining cardiovascular effects following acute COVID-19 illness. Notably, a retrospective study of 1914 patients found that among those presenting with acute coronary syndrome, there was a higher incidence of cardiomyopathy during the pandemic (March - April 2020) than prior to the pandemic (rate ratio = 4.58 [95% CI, 4.11-5.11]). There is speculation that this finding relates to pandemic-associated anxiety, as all patients diagnosed with cardiomyopathy tested negative for COVID-19 on admission.
This finding raises an important consideration regarding the etiology of many cardiovascular sequelae of acute COVID-19 infection, including stress cardiomyopathy.
Cardiac dysfunction and heart failure
There is some evidence suggesting an increased risk of heart failure beyond the first 30 days after SARS-CoV-2 infection.
Although the risk is not limited to hospitalized patients, patients admitted to intensive care units (ICU) have the highest risk, followed by hospitalized non-ICU patients and non-hospitalized patients.
The impact of COVID-19 disease on heart failure may be due to the long-term effects of SARS-CoV-2 on cardiac function, residual adverse effects of cardiac involvement in acute COVID-phase, or the worsening of previous cardiovascular disease post-infection.
Patients with underlying conditions may be particularly at risk of cardiovascular complications after acute COVID-19 illness. In patients with a history of ST elevation myocardial infarction (STEMI), there were higher rates of major cardiovascular and cerebrovascular events (MACCE) and hospitalization with heart failure among those who tested positive for COVID-19 versus those who did not. However, there was no difference in long-term mortality between STEMI patients with or without a COVID-19 infection.
Some studies have not found evidence of cardiac dysfunction following acute COVID-19 illness. In a cross-sectional study of 105 patients who were hospitalized for COVID-19, structural and functional cardiac characteristics on echocardiography were similar to matched controls at a median of 41 days from COVID-19 diagnosis.
Findings were also similar between patients who experienced severe and mild acute COVID-19 illness. In another short-term study, normal LV and RV function on echocardiography was found in most patients 6 weeks after discharge from hospital due to SARS-CoV-2 infection.
The normal findings in these studies may be due to the short duration of follow-up (<2 months). Indeed, while subclinical myocardial injury may appear early on, changes in cardiac function like diastolic dysfunction can present later. It has been reported that while cardiac MRI and ECG changes are often observed within the first 3 months after SARS-CoV-2 infection, echocardiography changes often present in 3-6 months.
LV dysfunction has been observed after acute COVID-19 illness. Indeed, several studies have observed statistically significant reductions in left ventricular ejection fraction (LVEF) compared to controls 2-9 months post-acute COVID-19 illness, including patients with acute disease ranging from asymptomatic to severe.
Moreover, congestive heart failure and a prominent reduction in LVEF (mean LVEF 28%) has been observed in patients with biopsy-proven post‐COVID-19 myocarditis at an average of 5.5 months following COVID‐19 infection.
There are also reports of subclinical LV dysfunction after COVID-19 diagnosis among patients at low cardiac risk who reported their SARS-CoV-2 infection as asymptomatic and recovered from acute symptoms at home.
In other cases, echocardiography testing has not shown changes in EF after acute SARS-CoV-2 infection. For example, in a study of COVID-19 patients with no previous cardiovascular disease who presented with elevated cardiovascular biomarkers on admission, there was no difference in LVEF, LV diameters, LV mass, or LA volumes in echocardiograms performed at a median 4.3 months after discharge compared to those without elevated markers.
None of the patients died or were admitted due to heart failure at their median 7-month follow-up. In Dennis et al.’s study of 201 long COVID patients with a low rate of acute COVID-19 hospitalization and comorbidities, LVEF and LV end-diastolic volume were not significantly different between long COVID patients and healthy controls.
Similarly, while Lassen et al. showed a reduction in LVEF 2 months after hospitalization for acute COVID-19 illness, it was not significantly different from the control group.
A possible explanation for null LVEF findings is that LVEF testing may not be sensitive enough to detect cases of minor LV impairments. Studies show that measure of LV longitudinal strain (LVLS) has a higher sensitivity for detecting minor LV myocardial function impairment compared to measure of LVEF.
This difference can be explained by the fact that LVEF is dependent on both myocardial function and volume load, whereas LVLS is affected mostly by myocardial function.
In a cohort of 153 hospitalized patients who received an echocardiogram at baseline and at a mean follow-up of 129 days, a pattern of normalization and regression to mean in LVEF was shown.
LVEF decreased in those with an elevated baseline LVEF (which could be due to an adaptive physiological response to stress during acute COVID-19 illness), those with reduced baseline LVEF improved at follow-up, while those with normal baseline LVEF remained normal. On the other hand, results from LVLS showed a reduction in those with normal baseline measures, potentially revealing a higher sensitivity of LVLS measure to LV impairments.
In addition to LV systolic dysfunction, LV diastolic dysfunction has also been reported. One study among patients who experienced myocardial injury during the acute COVID-19 illness found significant cardiac diastolic abnormalities without systolic involvement 6 months after hospitalization.
Resting echocardiographic results were similar between those who had myocardial injury and elevated cardiac markers in the acute phase versus those who did not. However, exercise induced an increased E/e’ ratio (an indicator of left ventricular filling pressure) and systolic pulmonary artery pressure in the patients who had myocardial injury during acute COVID-19 illness compared to those without myocardial injury. The changes in left ventricular diastolic markers were not associated with cardiovascular risk factors, leaving COVID-19 illness as a potential cause. It is suggested that the increased E/e’ ratio post-COVID is due to the myocardial inflammation that can initiate tissue fibrosis and stiffness. This change can affect cardiac relaxation and diastolic function in the long term.
. Dysfunction has been shown with reduction in RV global longitudinal strain (RV-GLS), right ventricle free wall longitudinal strain (RV-FWLS), and tricuspid annular plane systolic excursion (TAPSE).
Additionally, Maestre-Muñiz et al. observed 2.7% right heart failure in a study of patients 1-year post-hospitalization for SARS-CoV-2 infection. This finding was not associated with previous cardiac risk factors, with new-onset hypertension, nor with left heart failure.
Meanwhile, other studies have shown that echocardiographic measures of RV function such as TAPSE and RVLS improve following the resolution of acute COVID‐19 illness.
Despite resolution of acute abnormalities in ventricular size or function, a 29% rate of persistent adverse ventricular remodeling has been observed at 3 months following hospitalization.
Different explanations have been proposed for the development of RV dysfunction after acute COVID-19 illness. Akkaya et al. found a decrease in RV-GLS and RV-FWLS at 3 months was negatively correlated with acute-phase levels of C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), d-dimer, ferritin, and platelet to lymphocyte ratio (PLR). These markers are indicators of inflammation and thrombosis, and point to the possible pathology behind RV dysfunction, including a combination of reduced contractility due to myocardial damage and increased right ventricular afterload. This study also showed an increase in RV diameter and systolic pulmonary artery pressure (sPAP) at 3 months following COVID-infection, suggesting the same mechanism.
However, RV dysfunction has also been shown in cases without increased afterload. In an Italian study of hospitalized patients with no history of cardiovascular or lung disease who recovered from severe acute COVID-19 illness, subclinical RV dysfunction by abnormal RV longitudinal strain was found without any evidence of pulmonary hypertension or increased RV afterload in 42% of patients 2-3 months post-COVID.
The incidence of RV dysfunction without increased afterload may point to reduced contractility as the main potential mechanism.
New onset hypertension
New onset hypertension has been observed following acute COVID-19 illness. For example, of 543 patients who were hospitalized or discharged from an emergency department for COVID-19, 12 (2.2%) had onset of high blood pressure in the following year.
However, as no control group was included, it is unclear whether this incidence exceeds expected levels. Further, this finding may relate to pandemic stress rather than SARS-CoV-2 infection. Another study found that 1.3% of patients (n=538) developed hypertension by approximately 3 months following hospital discharge for COVID-19.
Although comparison to controls did not reach statistical significance (p=0.2), none of the patients in the control group (n=184) developed hypertension in the same timeframe. Neither study formally evaluated new onset hypertension through repetitive blood pressure measurements, and instead relied primarily on medical records and patient report.
It is concerning that new onset hypertension has been observed even among young and previously healthy patients. One study of young adults (mean [SD] age: 21[20-22]) found prolonged impact on systolic and mean arterial blood pressure following acute COVID-19 illness, with gradual improvements seen 6 months post-infection (e.g., mean systolic pressure at 1-month post-infection: 112 [+/- 7] mmHg vs. at 6 months: 101 [+/- 8] mmHg, p=0.008).
Szeghy RE, Stute NL, Province VM, et al. Six-month longitudinal tracking of arterial stiffness and blood pressure in young adults following SARS-CoV-2 infection. J Appl Physiol (1985). 2022;132(5):1297-1309. doi:10.1152/japplphysiol.00793.2021
Of interest, an observational study examining blood pressure 12 months or more after SARS-CoV-2 infection is currently underway (Longer-term effects of SARS-CoV-2 Infection on blood vessels and blood pressure [LOCHINVAR; NCT05087290].
Rationale and Design for the LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure (LOCHINVAR): an observational phenotyping study.
This investigation extends a pilot study that found patients hospitalized for COVID-19 showed an average 8.6 mmHg increase in blood pressure after SARS-CoV-2 infection compared to controls 12 or more weeks after discharge (NCT04409847).
Although evidence remains limited, some recent studies have reported pulmonary hypertension (PH) following acute COVID-19 illness. Tudoran and colleagues found that of 91 patients hospitalized for moderate COVID-19, 7 patients (7.69%) were diagnosed with PH two months after discharge.
Notably, all patients were younger than 55 years of age, had no history of cardiovascular pathology, and did not require mechanical ventilation during hospitalization. Development of PH in the 6 to 12 weeks following relatively severe COVID-19 illness has also been described in case reports.
Several pathologies may explain predisposition to PH after recovery from acute SARS-CoV-2 infection. Thickening of pulmonary arterial walls has been observed histologically in patients who died of COVID-19,75 revealing potential susceptibility of COVID-19 patients to future pulmonary arterial hypertension. Development of PH after acute COVID-19 illness has also been linked to increased inflammatory markers during hospitalization,
The possible implication of endothelin in the pathology of COVID-19-induced pulmonary hypertension”: Endothelin and COVID-19-induced pulmonary hypertension.
There are several proposed mechanisms regarding the development of cardiovascular outcomes following acute COVID-19 illness. Regarding acute SARS-CoV-2 infection, one of the main proposed mechanisms for development of cardiovascular complications is the Angiotensin-Converting Enzyme 2 (ACE2) and its interactions with the Renin-Aldosterone System (RAAS) and Kinin-Kallikrein System (KKS). The ACE2 receptor is expressed throughout the body, and is present in approximately 7.55% of myocytes.
Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.
COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 may bind and activate TLR4 to increase ACE2 expression, facilitating entry and causing hyperinflammation.
The S1 subunit of the SARS-CoV-2 spike protein binds the ACE2 receptor on the cell surface and allows the virus to enter the cell membrane. This results in a downregulation of the ACE2 receptor.
Augustine R, S A, Nayeem A, et al. Increased complications of COVID-19 in people with cardiovascular disease: Role of the renin–angiotensin-aldosterone system (RAAS) dysregulation. Chem Biol Interact. 2022;351. doi:10.1016/j.cbi.2021.109738
Typically, the RAAS pathway begins with renin and produces angiotensin II. Angiotensin II functions with Angiotensin Type-1 Receptor (AT1R) to induce vasoconstriction, fibrosis, and apoptosis, as well as to elevate blood pressure, facilitate cardiac hypertrophy, and increase heart rate.
ACE2 converts angiotensin II to Ang 1-7 and Ang 1-9 which further interact with G-protein Coupled Receptors (GPCRs) to have the opposite effect of angiotensin II. This allows for a balanced activation and deactivation response. SARS-CoV-2 infection leads to negative regulation of the ACE2 receptor, causing angiotensin II accumulation and hemostatic imbalance through activation of the coagulation cascade, impaired fibrinolysis, and thrombin generation.
Figure 2Schematic of a possible mechanisms for downregulation of ACE2 by SARS-CoV-2 infection and its downstream consequences., ACE2 = Angiotensin-Converting Enzyme II, AT1R = Angiotensin Type-1 Receptor
Another downstream product of inflammatory pathways is the bradykinin storm of KKS, which normally causes vasodilation and regulates tissue repair, inflammation, cell proliferation, and platelet aggregation. Kallikreins serine proteases cleave kininogens to release bradykinin and kallidin. Downstream, they activate bradykinin-1 and bradykinin-2 receptors to increase blood flow and have anti-thrombogenic effects. ACE2 mediates the conversions in this pathway as well, meaning downregulation of ACE2 during SARS-CoV-2 infection prevents the counterbalancing action of the KKS system.
Excessive pressure increase and constriction of blood vessels can raise the risk of chronic hypertension and thrombosis. In the peripheral blood vessels, pressure and constriction causes an afterload on the heart.
Furthermore, the potential of the RAAS and KKS pathways to induce a cytokine or bradykinin storm has been proposed as a mechanism for the development of cardiovascular consequences of long COVID.
Activation of CD4+ T cells by viral infection can also cause the release of pro-inflammatory cytokines and interferon. Particularly, IL-6 and TNFα induce the cytokine storm. Hyperinflammation creates a feedback cycle of tissue damage, stimulating greater inflammatory response.
The response may also involve the Toll-like Receptor 4 (TLR4) cell surface immune receptor. The SARS-CoV-2 spike glycoprotein has been shown to have high protein-protein affinity to TLR4.
COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 may bind and activate TLR4 to increase ACE2 expression, facilitating entry and causing hyperinflammation.
COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 may bind and activate TLR4 to increase ACE2 expression, facilitating entry and causing hyperinflammation.
A prolonged version of this reaction is a proposed mechanism for long COVID. TLR4 receptors are also present on activated CD4+ and CD8+ T cells and can induce inflammatory cytokines. A dysregulation of the adaptive immune system, particularly involving CD4+ and CD8+ T cell exhaustion or upregulation, could cause long COVID symptoms,
A longitudinal follow-up of COVID-19 patients in the convalescent phase showed recovery in radiological results, the dynamics of lymphocytes, and a decrease in the level of IgG antibody: a single-centre, observational study.
Their CD8+ T lymphocytes returned to normal 4 months after symptom onset while CD4+ lymphocytes remained low in half of the patients.
Lingering vasculopathy after acute SARS-CoV-2 infection can also lead to long-term cardiovascular complications. The endothelium of tissues serves as a barrier, has antithrombotic properties and contributes to vascular tone. Inflammation of the endothelium (endotheliopathy) can negatively impact these functions. In the heart, this can induce thrombosis and myocardial injury leading to reduced functionality.
In a study of 80 individuals with long COVID symptoms, all participants had micro clots in their samples, suggestive of endotheliopathy and a disrupted clotting state.
Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC).
Circulating endothelial cells have also been measured in post-COVID patients, indicating that vessel injury is persistent in those recovering from viral infection.
Mitochondrial stress response is another proposed mechanism to explain long COVID symptoms. Significantly altered levels of proteins originating from the mitochondria have been observed at 40 days following SARS-CoV-2 infection, suggesting continued mitochondrial stress.
‘The long tail of Covid-19’ - The detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients.
When under stress, impaired mitochondrial function reduces metabolism and increases cardiomyocyte fatigue. Consequently, cardiac systolic and isovolumic times increase, reducing cardiac performance.
Viral load may also be associated with development of long COVID. In the acute phase, high viral loads have been found in the myocardium, and have been associated with increased cytokine levels.
Persistence of viral reservoirs may lead to chronic inflammation and has been proposed as a potential explanation for ongoing cardiac symptoms after acute illness.
Resultant chemokines may cause damage via reactive oxidative species and lead to prolonged long COVID pathology.
Some studies have also found an association between higher antibody levels against SARS-CoV-2 and cardiopulmonary symptoms in long COVID patients. Cardiopulmonary symptoms have been more closely associated with antibody levels rather than with myocardial dysfunction and injury, as troponin levels were low or undetectable at a median of 7.2 months following SARS-CoV-2 infection.
Another proposed mechanism suggests that autoantibodies alongside localized inflammation may be involved in microvascular thrombosis leading to exacerbated long COVID symptoms.
Many sequelae of post-acute COVID-19 illness can also be considered as associated with the cardiometabolic syndrome, yet the exact nature of the association is unclear. Prolonged inflammation and tissue damage from acute infection have been suggested as promoters of cardiometabolic syndrome-associated diseases seen after COVID-19 illness, including diabetes and heart failure.
For example, the long-established link between inflammation and expansion of atherosclerotic plaque may explain development of atherosclerosis among patients who have recovered from acute SARS-CoV-2 infection.
Although there is a lack of evidence on hyperlipidemia in the post-COVID period, evidence of abnormal lipid levels has been observed in patients over a decade after the emergence of SARS-CoV-1 in 2002.
raise concerns about the potential long-term impacts of COVID-19 on lipid metabolism. Further research is needed to elucidate the connection between cardiometabolic syndrome-associated diseases after acute COVID-19 disease.
Conclusion
This review highlights evolving evidence on the potential cardiovascular complications after recovery from acute COVID-19 illness, as well as proposed underlying mechanisms. Cardiovascular complications may arise from damage during acute infection, outcomes resulting from ongoing inflammation, and exacerbation of pre-existing conditions. Commonly reported outcomes include both ischemic and non-ischemia myocardial injury, cardiac dysfunction, arrhythmias and dysautonomia. Of concern, long-term outcomes including myocarditis and POTS have been observed in otherwise low-risk patients who experienced mild disease, highlighting the need for vigilance even in young, healthy populations. Although some studies show improvement over time, continued follow-up with long COVID patients will be needed to better characterize long-term outcomes.
This review adds to the growing body of literature summarizing post-acute cardiovascular outcomes of COVID-19, with a focus on outcomes occurring longer than 1 month after acute illness. In organizing our review by specific outcomes, we draw attention to the breadth of potential cardiovascular complications. Although current evidence remains limited in quantity and quality, we hope this review will encourage clinicians to be mindful of potential cardiovascular risks and can serve as a starting point for future investigations.
DISCLOSURES
None of the authors have any personal potential conflicts of interests. MediciNova is providing an investigational drug for the RECLAIM trial, an interventional trial of long COVID, of which AM Cheung is the Principal Investigator.
FUNDING SOURCES
This review is partially supported by a CIHR Grant: VR4-172729. AM Cheung is supported by a Tier 1 Canada Research Chair.
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Severe acute respiratory syndrome-associated coronavirus nucleocapsid protein interacts with Smad3 and modulates transforming growth factor-beta signaling.
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Szeghy RE, Stute NL, Province VM, et al. Six-month longitudinal tracking of arterial stiffness and blood pressure in young adults following SARS-CoV-2 infection. J Appl Physiol (1985). 2022;132(5):1297-1309. doi:10.1152/japplphysiol.00793.2021
Rationale and Design for the LOnger-term effects of SARS-CoV-2 INfection on blood Vessels And blood pRessure (LOCHINVAR): an observational phenotyping study.
The possible implication of endothelin in the pathology of COVID-19-induced pulmonary hypertension”: Endothelin and COVID-19-induced pulmonary hypertension.
Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.
COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 may bind and activate TLR4 to increase ACE2 expression, facilitating entry and causing hyperinflammation.
Augustine R, S A, Nayeem A, et al. Increased complications of COVID-19 in people with cardiovascular disease: Role of the renin–angiotensin-aldosterone system (RAAS) dysregulation. Chem Biol Interact. 2022;351. doi:10.1016/j.cbi.2021.109738
A longitudinal follow-up of COVID-19 patients in the convalescent phase showed recovery in radiological results, the dynamics of lymphocytes, and a decrease in the level of IgG antibody: a single-centre, observational study.
Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC).
‘The long tail of Covid-19’ - The detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients.
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