COVID-19 was primarily identified as a respiratory illness, but reports of patients presenting initially with cardiovascular complaints are rapidly emerging. Many patients also develop cardiovascular complications during and after COVID-19 infection. Underlying cardiovascular disease increases the severity of COVID-19 infection; however, it is unclear if COVID-19 increases the risk of or causes cardiovascular complications in patients without preexisting cardiovascular disease. The review is aimed at informing the primary care physicians of the potential cardiovascular complications, especially in patients without underlying cardiovascular disease. A comprehensive literature review was performed on cardiac and vascular complications of COVID-19. The primary cardiac and vascular complications include myocarditis, acute coronary syndrome, myocardial injury, arrhythmia, heart failure, shock, multisystem inflammatory syndrome, venous and arterial thrombotic events, stroke, and coagulopathy. A detailed analysis of the pathogenesis revealed six possible mechanisms: direct cardiac damage, hypoxia-induced injury, inflammation, a dysfunctional endothelial response, coagulopathy, and the catecholamine stress response. Autopsy reports from studies show cardiomegaly, hypertrophy, ventricular dilation, infarction, and fibrosis. A wide range of cardiac and vascular complications should be considered when treating patients with confirmed or suspected COVID-19 infection. Elevated troponin and natriuretic peptides indicate an early cardiac involvement in COVID-19. Continuous monitoring of coagulation by measuring serum D-dimer can potentially prevent vascular complications. A long-term screening protocol to follow-up the patients in the primary care settings is needed to follow-up with the patients who recovered from COVID cardiovascular complications.
The World Health Organization (WHO) describes coronaviruses as a group of viruses, several of which infect humans, which usually cause respiratory disease or illness, ranging from the common cold to severe acute respiratory distress syndrome (ARDS) [
Dweck et al. (2020) demonstrated that the cardiovascular system seems to be one of the most common organ systems affected by COVID-19. After excluding patients with preexisting ischemic heart disease, heart failure, and valvular heart disease, 46% of patients with COVID-19 with an indication for echocardiography (suspected left ventricular failure, suspected right heart failure, and elevated cardiac biomarkers) had echocardiographic abnormalities including myocardial infarction, myocarditis, and Takotsubo cardiomyopathy [
COVID-19 can also manifest as vasculopathy. Recent studies have shown the impact that COVID-19 has had on increasing the risk of coagulopathies, including thrombotic events such as deep venous thrombosis (DVT), coagulopathy, and stroke [
This review intends to provide the primary care physicians with concise knowledge of potential cardiovascular complications in COVID-19 patients to understand the disease course better and decide how to manage and treat patients. Major common cardiac and vascular complications in COVID-19 patients were investigated, with an emphasis on those without known underlying cardiovascular disease. The authors expect this review will contribute to the intake and management of patients with suspected and confirmed COVID-19 infection making evaluation and treatment safer and more efficient. The aim is to ensure physicians are up to date on the cardiovascular complications that can arise from COVID-19.
The exact mechanism by which COVID-19 causes myocardial injury and damage is being investigated. Kim et al. proposed six different mechanisms by which COVID-19 infection may cause cardiovascular injury and manifestations [
To summarize, direct injury, hypoxia, microvascular damage, and systemic inflammatory syndrome may all lead to inflammation of the heart, myocarditis, and acute cardiac injury.
Myocarditis and acute cardiac injury further complicate the infection with the potential to lead to arrhythmia, heart failure, and cardiogenic shock [
Cardiac complications.
Eiros et al. [ | Richardson et al. [ | Bhatraju et al. [ | Shi et al. [ | Chen et al. [ | Li et al. [ | Wang et al. [ | Liu et al. [ | Ruan et al. [ | Guan et al. [ | Arentz et al. [ | Huang et al. [ | Wang et al. [ | Yang et al. [ | Zhou et al. [ | Guo et al. [ | Grimaud et al. [ | Stefanini et al. [ | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
139 | 5700 | 24 | 416 | 274 | 1527 | 339 | 137 | 150 | 1099 | 21 | 41 | 138 | 52 | 191 | 187 | 20 | 28 | |
Age | 52 (median) | 63 (median) | 64 (median) | 64 (median) | 62 (median) | n/a | 71 (mean) | 57 (median) | 47 (median) | n/a | 49 (median) | 56 (median) | 60 (mean) | 56 | 59 (mean) | 10 (mean) | n/a | |
Cardiac symptoms | ||||||||||||||||||
Chest pain | 29% | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — |
Palpitations | 32% | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — |
Clinical findings | — | |||||||||||||||||
CMR abnormalities | 75% | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — |
ECG abnormalities | 50% | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — |
Cardiomyopathy | — | — | — | — | — | — | — | — | — | — | 33% | — | — | — | — | — | — | — |
Myocarditis | 37% | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | 100% | — |
Myocardial infarction | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | 100% |
Cardiac injury biomarkers | — | — | — | 20% | 44% | 8-12% | 21% | — | 40% ( | — | — | 12% | 7% | 23% | 17% | 28% | — | — |
Elevated troponin | — | 23% | 15% | 20% | 41% | — | — | — | — | — | — | 12% | — | — | 17% | 28% | — | — |
Arrhythmia | — | — | — | — | — | 10% | — | — | — | — | 17% | — | — | 6% | 100% | — | ||
Heart failure | — | — | — | — | 24% | — | 17% | — | — | — | — | — | — | 23% | — | — | ||
Shock | — | — | — | — | — | 2% | — | — | 1% | — | 7% | 9% | — | — | — | — | ||
Coagulopathy | — | — | — | — | — | — | — | — | — | — | — | 19% | 34% | — | ||||
Medications | ||||||||||||||||||
Antibiotic use | 41% | — | — | — | 91% | — | — | — | 95% | — | — | — | 18% | — | — | 98% | — | — |
Antiviral use | 12% | — | — | — | 86% | — | — | — | 59% | — | — | — | 90% | — | — | 89% | — | — |
Mechanical ventilation | — | 12% | 75% | — | 43% | — | — | — | 17% | 2% | 71% | 10% | 12% | 42% | 17% | 24% | 40% | — |
ICU | — | 23% | 100% | — | — | — | — | — | 27% | 5% | 100% | 32% | 26% | 100% | 26% | — | 100% | 4% |
Non-ICU | — | 77% | 0% | — | — | — | — | — | 73% | 95% | 0% | 68% | 74% | 0% | 74% | — | 0% | 96% |
Comorbidities | ||||||||||||||||||
Hypertension | 12% | 57% | — | 31% | 34% | 17% | 41% | 10% | — | 15% | — | 15% | 31% | — | 30% | 33% | — | 71% |
CV disease | 6% | — | — | — | — | — | 14% | 7% | — | — | — | 15% | 15% | 10% | — | — | — | — |
Dyslipidemia | 19% | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — |
Coronary artery disease | — | 11% | — | 11% | 8% | — | — | — | — | 3% | — | — | — | — | 8% | 11% | — | — |
CHF | — | 7% | — | 4% | — | — | — | — | — | — | — | — | — | — | — | — | — | — |
Cardiomyopathy | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | 4% | — | — |
Previous MI | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | 11% |
Survived | — | 5147 | 12 | 359 | 161 | — | 274 | 121 | 82 | 1084 | 10 | 35 | 132 | 20 | 137 | 144 | 20 | 17 |
Death | — | 553 | 12 | 57 | 113 | — | 65 | 16 | 68 | 15 | 11 | 6 | 6 | 32 | 54 | 43 | 0 | 11 |
Myocarditis has many different causes, including infection (viral, bacterial, etc.), autoimmune disease (SLE, etc.), and medications. Myocarditis can also be idiopathic. Inflammation seen in myocarditis can be focal or global, can lead to chamber dysfunction or necrosis, and has the potential to cause chronic cardiovascular complications [
The clinical presentation of COVID-19 is like the myocarditis of any etiology and includes fever, hypotension, dyspnea, chest pain, and arrhythmia. Viral myocarditis may also mimic myocardial infarction, acute coronary syndrome, or heart failure with nonspecific electrocardiographic changes (ST elevation, T-wave inversion, ST depression, and pathologic Q-waves), elevated enzymes, hemodynamic instability, tachycardia, displaced point of maximal impulse, or S3/S4 gallop. Myocarditis may also progress to heart block, arrhythmia, and impairment of left ventricular function [
Myocarditis, of any cause, is often preceded by flu-like and gastrointestinal symptoms. These are also some of the most common presenting symptoms of patients with COVID-19, making the diagnosis and management of the disease process tricky [
Fulminant myocarditis and heart failure have also occurred in COVID-19-infected patients [
A study of 1,216 patients with COVID-19 infection showed that 55% of patients that received an echocardiogram (due to suspected left or right heart failure, chest pain with ST-elevation, cardiac biomarker elevation, ventricular arrhythmia, suspected tamponade, or cardiogenic shock) had an abnormal echocardiogram. Left ventricular abnormalities were seen in 39%, and right ventricular abnormalities were seen in 33%. Evidence for myocardial infarction was seen in 3%, and evidence of myocarditis was seen in 3%. Of the 1216 patients, 901 (74%) patients did not have an underlying cardiac disease; still, 46% of them had abnormal echocardiograms, and 13% had severe disease. 25% of those without the preexisting cardiac disease had abnormal left ventricles, 33% had abnormal right ventricles [
Increased risk for thrombotic events can lead to increased ACS risk in COVID-19 positive patients. Furthermore, upon onset of inflammation, ACS can be caused by plaque rupture due to macrophage activation, endothelial cell activation, smooth muscle cell activation, tissue factor expression, and further inflammation onset due to platelet activation [
Although the frequency remains unclear, myocardial injury with ST-segment elevation has been observed in COVID-19 patients. In a case series of 18 patients with COVID-19, 14 had focal ST-segment elevation, and four had diffuse ST-segment elevation. Ten patients had ST-segment elevation upon presentation. The other eight patients developed ST-segment elevation during hospitalization. Still, their treatment is unknown, and if it included azithromycin or hydroxychloroquine, it might have contributed to the development of rhythm abnormalities. Eight patients had a reduced left ventricular ejection fraction [
It is essential to note the overlapping disease course and symptomatology between ACS and COVID-19 [
The definition of myocardial or cardiac injury varies between studies, and no integrated definition is currently present. Varying definitions of myocardial injury are presented in Table
Definition and incidence of cardiac injury from COVID-19 studies.
Study | Patients ( | Cardiac injury definition | Incidence of cardiac injury in COVID-19 infection ( |
---|---|---|---|
Guo et al. [ | 187 | Elevated troponin-T | 52 (27.8%) |
Huang et al. [ | 41 | Elevated hs-troponin-I | 5 (12%) |
ECG | |||
Echo | |||
Wang et al. [ | 138 | Elevated troponin-I | 10 (7.2%) |
ECG | |||
Echo | |||
Yang et al. [ | 52 | Elevated hs-troponin-I | 12 (23%) |
Zhou et al. [ | 191 | Elevated troponin-I | 33 (17%) |
ECG | |||
Echo |
Elevated cardiac biomarker levels, myocardial inflammation, electrocardiographic abnormalities, and echocardiographic abnormalities are highly prevalent in patients with COVID-19. These signs are associated with a more severe disease course and a worse prognosis. Signs of myocardial injury have been seen in up to 30% of hospitalized COVID-19 patients [
Further research is needed to establish the clinical value of troponin levels in COVID-19-infected patients. Elevated troponin levels were associated with elevated levels of CRP and NT-proBNP, linking myocardial injury to the severity of inflammation and ventricular dysfunction [
Arrhythmias represent one of the complications of COVID-19 infection, demonstrated in 16.7% of patients with an increased prevalence of 44.4% in patients admitted to the ICU [
Myocarditis-induced arrhythmias have been seen in COVID-19 positive patients in an acute setting or chronic myocarditis [
Palpitations were one of the most common presenting symptoms in 7.3% of patients in a cohort of 137 COVID-19 patients [
The risk of arrhythmia could also be associated with the usage of early COVID-19 treatments such as azithromycin and hydroxychloroquine. The use of hydroxychloroquine and azithromycin has independently been shown to cause arrhythmia [
A higher incidence of out-of-hospital cardiac arrest has been noted in patients suspected of or with a confirmed diagnosis of COVID-19 [
Heart failure has been shown to occur in up to 23% of infected patients. They seem to occur secondary to exacerbation of left ventricular dysfunction, myocarditis, acute coronary syndrome, arrhythmia, pulmonary hypertension, ARDS, or cardiomyopathy [
The pediatric population appear to have a milder clinical course but may still show some cardiac complications such as arrhythmia and must be monitored [
A wide range of vascular complications has been recognized in patients affected with COVID-19 that include venous and arterial thrombosis, neurological ischemic events, and coagulopathy as summarized in Table
Vascular complications and pathology.
Study | Total population | Hearts studied | Mean/range age (years) | Cardiac comorbidities | Mean time to death | Cardiac enlargement | Other findings | Cardiac interstitial fibrosis | Epicardial mononuclear infiltrate | Myocardial infarction | Elevated D-dimer | Neurological vascular lesions | Venous thromboembolism | Other |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Bryce et al. [ | 67 | 25 | 69 (range 34-94) | Hypertension (62.7%), coronary artery disease (31.3%), heart failure (14.9%), atrial fibrillation (13.4%) | 9.5 days (range 0-61) from admission | Left ventricular hypertrophy (100%) | Myocyte hypertrophy and interstitial fibrosis | 100% | 60% | — | 80.6% | Cerebral infarct (30%) | 6% | Intravascular fibrin thrombi (25%), CD61 platelet aggregates or thrombi (31%), large pulmonary emboli (6%) |
Fox et al. [ | 10 (African American) | 9 | Range 44-78 | Hypertension (70%), atrial fibrillation (10%), heart failure (10%) | 8.2 days (range 0-25) from admission; 11.6 days from symptom onset | Right ventricular dilation | Scattered myocyte necrosis; no significant lymphocytic infiltration | — | — | — | 90% | — | — | Small, firm thrombi in peripheral parenchyma (100%) |
Tian et al. [ | 4 | 2 | Range 59-81 | Hypertension (25%) | 15-52 days from disease onset | — | — | 100% | — | — | — | — | — | |
Rapkiewicz et al. [ | 7 | 4 | Range 44-65 | Hypertension (85%), coronary artery disease (14%) | 12.9 days (range 3-25) from symptom onset; mean 4.4 days from admission | — | Megakaryocytes with fibrin microthrombi in cardiac microvasculature (7/7) | — | 25% | 25% | 100% | — | — | Pulmonary arterial thrombi (57%), venous thrombosis (29%), CD61 platelet aggregates or thrombi (100%) |
Bradley et al. [ | 12 | 12 | 70.4 | — | 7 days (range 1-14) from symptom onset | — | Myocyte hypertrophy (12/12) | 83% | — | — | — | — | — | Subsegmental pulmonary emboli (17%) |
Giacca et al. [ | 41 | 30 | Male -77; female -84 | — | — | — | — | — | — | Cardiomyocyte damage suggestive of hypoxic injury (54%) | 24% | — | — | Pulmonary thrombosis (77%) |
Edler et al. [ | 80 | 80 | Mean 79.2 | Cardiomyopathy (11.25%), arrhythmia (1.25%), cardiac insufficiency (38.75%), atrial fibrillation (18.75%), hypertension (31.25%) | — | — | — | — | — | — | — | — | 40% | Pulmonary embolism (21%) |
Lax et al. [ | 11 | 11 | Mean 80.5 (range 66-91) | Hypertension (81.8%), coronary artery disease (27.27%) | 8.55 days (range 4-18) from symptom onset | Biventricular hypertrophy (100%), biventricular dilation (91%) | — | 90.90% | — | — | 86% | — | — | Pulmonary arterial thrombosis |
Wichmann et al. [ | 12 | 12 | Mean 73 (range 52-87) | Coronary/ischemic heart disease (50%) | — | Biventricular hypertrophy (25%) | — | — | — | 50% | 71% | — | 58% | Pulmonary embolism |
In a recent study, 184 COVID-19 positive patients in the ICU were evaluated for thrombotic events. All the patients received standard doses of thromboprophylaxis following hospital protocol upon arrival [
In a case study, a COVID-19 positive patient was observed to have a severe case of venous thrombosis and arteriosclerosis obliterans of the lower extremities. The patient had a past medical history of uncontrolled type 2 diabetes. Upon arrival to the hospital, lab report showed marked C-reactive protein increase and elevated D-dimer level of over eight ug/mL with a normal PT and aPTT. Vascular ultrasound found DVT in the left lower extremity (LLE) and dorsalis pedis artery occlusion in the LLE on arrival. Anticoagulation and other supportive therapy were given, and after three days, vascular ultrasound confirmed bilateral lower extremity thrombosis with arterial tibialis anterior occlusion and dorsalis pedis artery occlusion on both lower extremities. This patient specifically had many risks and predispositions for DVT, however, it should be anticipated that an infection like COVID-19 could encourage an even greater hypercoagulable environment as seen with this patient who after three days developed many more clots [
Three of four COVID-19 patients in another case series had dermal arterial thrombosis suggestive of antiphospholipid syndrome, one also developed venous thrombosis, and all four patients had elevated D-dimer [
Additionally, certain types of rashes in COVID-19 patients may be an early clinical sign of an underlying thrombotic or hypercoagulable state [
Mao et al. (2020) studied 214 patients that tested positive for COVID-19, and of these patients, 36.4% were found to have neurologic symptoms. 41.1% of the patients in this study were severely infected. They had a higher prevalence of nervous system events such as ischemic stroke and cerebral hemorrhage, as well as symptoms of impaired consciousness. They also had high white cell count, high neutrophil count, lower lymphocyte counts, and elevated C-reactive protein (CRP) levels when compared to patients with nonsevere infection [
In a case study in Wuhan, China, three critically ill patients that tested positive for COVID-19 were observed to have coagulopathies. Imaging showed that all three COVID-19 positive patients developed multiple cerebral infarcts. Patient 3 developed a thrombotic event 18 days from disease onset, while patients 1 and 2 developed thrombotic events 18 and 33 days after disease onset, respectively. All the patients showed leukocytosis, thrombocytopenia, elevated fibrinogen, elevated d dimer, and presence of anticardiolipin IgA antibody and anti-B2 glycoprotein IgA and IgG antibodies [
A retrospective study looked at four COVID-19 positive patients that presented with acute stroke. All patients had hypertension. This may suggest the importance of considering comorbidities, especially hypertension, when analyzing patients for risk of mortality due to COVID-19 presenting with stroke. Two of the patients presented with left shift
During the outbreak of COVID-19 in Wuhan, China, abnormal coagulation patterns were recorded by some investigators. One case study investigated 183 patients who were confirmed COVID-19 positive [
COVID-19 patients presenting with vasculopathies often had abnormal PT/aPTT, D-dimer, and platelet counts [
Elevated C-reactive protein was also found in some patients presenting with COVID-19 [
Many studies have reported cardiac autopsy findings in COVID-19 patients (Table
The presence of SARS CoV-2 RNA was found in the autopsied hearts [
The National Health Commission of China (NHC) has shown some patients with later confirmed COVID-19 first presented to the doctor because of cardiovascular symptoms such as heart palpitations and chest tightness [
The NHC showed that 11.8% of patients without the underlying cardiovascular disease had substantial heart damage with elevated troponin levels and cardiac arrest [
Evaluation of cardiac manifestations in all COVID-19 confirmed or suspected cases is recommended to include but not limited to cardiac symptoms, chest X-ray or CT, unstable vital signs, cardiac biomarkers (ULN of CK-MB, Tn-I, Tn-T), electrocardiography, and echocardiography. It has been shown that cardiovascular complications in COVID-19 infection indicate a worse prognosis [
A cohort of 100 COVID-19-recovered patients showed independent of preexisting conditions, CMR evidence of cardiac involvement in 78%, and ongoing myocardial inflammation in 60% of patients 2 to 3 months after diagnosis [
While often bacterial, an increased risk of cardiovascular disease and complications has been linked to pneumonia in a 10-year follow-up study [
Acute cardiac injury is a common cardiovascular complication of COVID-19, and it occurs from direct myocardial injury, inflammation, myocardial oxygen supply, and demand mismatch, acute coronary events, and can be iatrogenic or from other unknown causes. Acute coronary events do not appear to be well documented but could result from plaque rupture or aggravation of the preexisting coronary disease. Heart failure can also result from myocardial injury or dysfunction or increased metabolic demand due to systemic disease, causing an acute decompensation of preexisting heart failure. Arrhythmia seems to occur in both mild and severe cases. However, little is known about the clinical value of these complications and manifestations of heart disease in COVID-19. Biomarker elevation, cardiac injury, and other cardiac sequelae may reflect the systemic disease and clinical course of COVID-19 infection.
Prolonged PT and aPTT, elevated d-dimer levels, and increased fibrin degradation levels are linked to a higher risk of mortality in COVID-19 patients. The mentioned lab values, excluding the PT/aPTT, signify a hypercoagulable state in a patient, which indicates potential thromboembolism. VTE has frequently been reported, and, upon presentation, patients with suspected and confirmed COVID-19 infection should be assessed for VTE risk. In treating patients with COVID-19, antiplatelet and anticoagulation therapies should be considered. Continued monitoring for signs of cardiac damage and coagulation (D-dimer) can help predict and potentially prevent COVID-19 complications.
The cardiovascular system is involved early in the disease course reflected in the release of prognostic and highly sensitive troponin and natriuretic peptides. Still, the actual time of onset of cardiovascular complications and symptoms has not been formally evaluated, leaving room for improvement in future research. Developing a cardiovascular screening protocol for COVID-19-recovered patients is crucial for monitoring the patients on a long-term basis by the primary care physician.
The authors declare no conflicts of interest.
Aaron Schmid, Marija Petrovic, Kavya Akella, and Anisha Pareddy conceived the idea of the review; Aaron Schmid initiated the design of creating the manuscript; all the authors were involved in literature search and review, writing, revision, and final approval of the manuscript.
The authors would like to acknowledge Daniel Gelfman, MD, for his time in reviewing and providing thoughtful guidance.