The COVID-19 pandemic has created a number of diagnostic challenges for clinicians and laboratorians world-wide. Even during the relatively quiet “off-peak” periods of acute COVID, there remain the challenges of helping the large group of patients left with the shrapnel of “long Covid.” Kaufman and Meyer, in a recent edition of this journal,1 present an excellent overview of the evolving long-term health consequences of COVID-19. This article will focus on the cardiovascular elements of acute COVID and long COVID with an emphasis on how deployment of known cardiovascular biomarkers can help aid in the identification, risk-stratification and treatment of patients.
While COVID-19 is primarily thought of as a respiratory illness, it became apparent early in the pandemic that the cardiovascular system is not spared from the effects of the disease. This makes sense mechanistically as the virus gains entry to human cells via the angiotensin-converting enzyme2 (ACE2), which is ubiquitously present in the body, including the cardiovascular epithelium. Additionally, it became quickly clear that patients with preexisting cardiovascular conditions were at higher risk for going on to develop severe COVID-19 disease.2 Similarly, patients hospitalized with severe COVID-19 even without pre-existing cardiovascular disease have had a significantly higher rate of cardiovascular complications such as myocardial infarction, heart failure, vascular thrombotic events, and myocarditis. Interestingly, myocarditis and heart failure can also be seen as rare but serious complications of mRNA COVID-19 vaccines absent any active viral infection, particularly in younger men.3 In all these patient groups, there is diagnostic and prognostic utility of cardiovascular biomarker management using necrosis markers (cardiac troponin), natriuretic peptides (BNP or nt-proBNP), and thrombosis markers (d-dimer).
Throughout the pandemic, a number of biomarkers have been identified to risk stratify patients presenting to the ER with COVID. In particular, either a troponin or a d-dimer value twice the upper limit of normal is associated with severe disease.5 Mueller and colleagues have published an overview of cardiovascular biomarkers in patients with COVID that helps differentiate some of the nuances in interpretation needed in patients with COVID.6
Troponin should be measured in hospitalized patients with COVID, and repeated if abnormal or if new clinical criteria arise. In non-critically-ill patients with COVID-19, modest elevations (up to 3 times the ULN) are often due to prior cardiac disease or myocardial ischemia related to respiratory failure. Higher concentrations (>3x ULN) are more likely to be due to the presence of specific acute cardiac disease such as myocardial infarction, myocarditis, or takotsubo syndrome.
Natriuretic peptides (NPs), such as BNP, nt-proBNP or MRpro-ANP should be measured if heart failure is suspected on clinical grounds. In patients who are not critically ill, NPs cut-offs for heart failure “rule-in” maintain high positive predictive value, even in patients with pneumonia. In contrast, currently recommended NP cut-offs should not be applied in critically ill in patients with ARDS or septic shock, as most critically-ill patients have substantial elevations in BNP/NT-proBNP, due to overwhelming hemodynamic decompensation.
D-dimers are generated by cleavage of fibrin monomers by plasmin, therefore, signal thrombus formation and resulting fibrinolysis. A d-dimer value lower than its assay specific cut-off has a high-negative predictive value to help rule out venous thromboembolism in low-risk patients. In more seriously ill patients, d-dimer can be used for the diagnosis and monitoring of disseminated intravascular coagulation associated with sepsis or shock. During the outbreak of COVID-19, a coagulopathy has been commonly observed in hospitalized patients that can be identified by d-dimer values. One mechanistic explanation is that severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) has a high affinity to endothelial cells and may induce ‘endotheliitis’, which could explain why d-dimer is higher in COVID pneumonia than other historically seen forms of pneumonia.7 Similar to the findings reported for cardiac troponin, in patients with COVID-19 the D-dimer values increase progressively in non-survivors whereas values remain around the upper limits of normal in survivors
In hospitalized patients with COVID, monitoring of coagulation parameters can aid to predict deterioration and potentially to guide therapeutic measures including the intensity of anticoagulation. Pharmacologic prophylaxis of venous thromboembolism (VTE) is recommended for all hospitalized patients with COVID (Kim). If VTE is suspected and detected, the patient’s anticoagulation should advance from prophylactic to therapeutic dosing. In summary, d-dimer testing sheds light on important pathophysiological aspects of COVID-19 disease as well as contributes to more effective early risk assessment, on guidance on intensity of anticoagulation.
Cardiovascular issues in long-COVID
Post-acute sequelae of SARS-CoV-2 infection (PASC) colloquially understood as “long-COVD” is currently defined by the U.S. CDC as “Broad range of symptoms (physical and mental) that develop during or after COVID-19, continue for ≥2 months (i.e., three months from the onset), and are not explained by an alternative diagnosis.”8 Cardiovascular complaints are common in long-COVID patients. Chest discomfort/pain is frequent and appears to resolve slowly. Chest discomfort persists in 12 to 22 percent of patients approximately two to three months after acute COVID-19 infection. There are a large number of diagnostic and therapeutic modalities being investigated in cardiovascular long-COVID.9 Suspected myocarditis and/or an unexplained troponin uncovered in a patient’s evaluation should lead to a cardiac MRI. In persistently dyspneic patients, natriuretic peptides should be part of the initial workup to investigate for superimposed heart failure on top of any pulmonary disease. Hypercoagulability states typically manifest during acute-COVID and not long-COVID. However, monitoring for persistent, refractory, or recurrent disease should be done when clinically indicated and this evaluation is usually initiated with a d-dimer.
We are also seeing a significant number of patients who are not suffering directly from COVID but have developed cardiovascular issues due to delaying care during the COVID-19 pandemic. Fear of being exposed to COVID-19 in healthcare settings has kept many patients from seeking care in Emergency Departments for potentially life-threatening issues. Also, many routine primary care and specialty care clinic visits have unfortunately been cancelled, postponed, or converted to video visits where important physical exam findings may not get properly discovered. One example of a direct risk would be a patient moving into a more severe stage of heart failure due to delayed diagnosis. Indirect risks are patients that have increased risk factors of COVID-19 complications such as advanced age, coronary heart disease, high blood pressure, stroke survivors, congenital heart defects, and compromised immune systems not getting the care they need in a timely manner. Cardiovascular experts from across the globe have weighed in on the delays to care and the backlog of potentially life-saving interventions and procedures, with a concerning impact on health for many members of society.4
While the detailed epidemiologic future of the COVID-19 pandemic remains unfinalized at this writing, this fearsome disease has changed many features of acute cardiovascular care. This has included important new understanding of pathological mechanisms, diagnostics, and therapeutics. Fortunately, a number of excellent cardiopulmonary biomarkers had been developed pre-pandemic; and their performance characteristics have been readily deployed by clinicians and researchers to optimize the identification and risk stratification of the more vulnerable subsets of COVID patients. Many have critiqued our preparedness and our tools used in the course of this pandemic. I would argue that laboratory medicine was better poised to handle the challenges of this pandemic than at any time in the last century. For instance, it is sobering to consider that, if this pandemic had occurred 30 years ago, many of the biomarkers and nucleic acid tests effectively deployed in our current arsenal, including the tests discussed in this article, would not have existed. An unprecedented amount of inflammation and thrombosis accompany this particular viral disease, which may account for much of its ferocious nature. Cardiac troponin, natriuretic peptides and d-dimer testing are three highly useful tools for the clinician to discern the extent of these pathologic processes and intervene as early as possible during the patient’s presentation. A “second punch” from COVID has come with the unusual features and complications of disease convalescence that we see in the group of patients suffering from long-COVID. Finally, access-to-care issues during the recent broad societal shutdowns have created a perfect storm of patients with brewing, advancing cardiovascular conditions for whom more rapid assessment and diagnostic evaluation will be essential in addressing these delayed, unaddressed health issues. Fortunately, there is a solid collection of cardiovascular tools already readily available to initiate the investigation and develop personalized treatment plans.
- Kaufman HW, Meyer III WA. The long-term health consequences of COVID-19. Medical Laboratory Observer. 2022;54(3):8-16.
- Giacca, M., Shah, A.M. The pathological maelstrom of COVID-19 and cardiovascular disease. Nat Cardiovasc Res (2022) 1, 200–210. doi.org/10.1038/s44161-022-00029-5.
- Bozkurt, B., Kamat, I., Hotez, PJ. (2021). Myocarditis with COVID-19 mRNA vaccines. Circulation, 2021 144(6), 471-484. doi: 10.1161/circulationaha.121.056135.
- Nicholls, M., The ongoing impact of COVID-19 on cardiovascular care. European Heart Journal (2021) 00, 1–3. doi: 10.1093/eurheartj/ehab244.
- Kim, AY, Gandhi, RJ In: Post TW, ed. UpToDate. UpToDate; 2022. Accessed March 22,2022. https://www.uptodate.com/contents/covid-19-management-in-hospitalized-adults
- Mueller, C., Giannitsis, E., Jaffe, A.S. et al. Cardiovascular biomarkers in patients with COVID-19. European Heart Journal Acute Cardiovascular Care, 2021 10(3), pp.310-319. doi: 10.1093/ehjacc/zuab009.
- Chen AT, Wang CY, Zhu WL et al. Coagulation Disorders and Thrombosis in COVID-19 Patients and a Possible Mechanism Involving Endothelial Cells: A Review. Aging and Disease. 2022 Feb;13(1):144. doi: 10.14336/AD.2021.0704.
- Mikkelson ME, Abramoff B In: Post TW, ed. UpToDate. UpToDate; 2022. Accessed March 22,2022 https://www.uptodate.com/contents/covid-19-evaluation-and-management-of-adults-following-acute-viral-illness
- Raman B, Bluemke DA, Lüscher TF, et al. Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus. European heart journal. 2022 Mar 14;43(11):1157-72. doi: 10.1093/eurheartj/ehac031.
Sean-Xavier Neath, MD, PhD Associate Physician, Emergency Medical Services Medical Affairs and Clinical Development University of California, San Diego.