Intermediate and Long-Term Impact of COVID-19 on Cardiovascular Disease
- COVID-19 infection has both intermediate and long-term consequences for the cardiovascular system.
- In acute infection, troponin elevation is more commonly a consequence of indirect cardiac injury from critical illness and multi-organ dysfunction than direct viral damage to the heart.
- In resolved infection, special attention should be paid to athletes at-risk for exercise-induced arrythmias, as well as survivors with residual cardiopulmonary symptoms.
Our understanding of the cardiovascular consequences of COVID-19, the disease stemming from infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is evolving rapidly. We are now at a unique juncture in the pandemic. The delay until herd immunity and emergence of variants will necessitate that the cardiology community remain up-to-date managing complications of acute infection. However, with vaccines now available, we can begin to devote some attention to long-term consequences for survivors.
Here, we review our current understanding of the implications of COVID-19 on the cardiovascular system, both in acute infection (mechanisms of cardiac injury, prognostic implications of troponin elevation, and role of cardiac magnetic resonance imaging [CMR]) and resolved infection (considerations for athletes and those with "long COVID").
I. Acute Infection
Mechanisms of Injury
Early in the pandemic, the prevalence of cardiac injury during acute COVID-19 emerged. The first studies from China described troponin elevation in 20-40% of hospitalized patients.1,2 Binding of COVID-19 to the angiotensin converting enzyme 2 (ACE2) protein found on the cellular membrane of cardiomyocytes raised theoretical concerns for direct viral injury and myocarditis.3 Recent pathology studies have now called into question myocarditis as a common mechanism of injury in COVID-19. In one of the largest cardiac pathology studies to date, zero cases met criteria for myocarditis.4
While COVID-19 has garnered special attention due to the frequency of troponin elevation seen, recent work by Metkus and colleagues showed that myocardial injury was actually less common in COVID-19 acute respiratory distress syndrome (ARDS) as compared to non-COVID-19 ARDS after correcting for the degree of critical illness.5 This suggests that myocardial injury in COVID-19 may not be unique to the virus's interaction with the heart, but rather the global organ dysfunction caused by the hyper-inflammatory physiology, supported by consistent associations between troponin and inflammatory markers (e.g., C-reactive protein, fibrinogen, ferritin) across several studies.1,5,6
Mechanisms of myocardial injury in COVID-19 can occur from oxygen supply-demand imbalance (particularly in the setting of underlying structural heart disease or coronary atherosclerosis) resulting from hypoxia, hypoperfusion, tachycardia, microvascular and macrovascular thrombosis, or inflammation-related injury. While more rare presentations of COVID-19 infection (e.g., stress cardiomyopathy, myocarditis, arrhythmia, or acute plaque rupture) should not be discounted, we are finding that more commonly, the heart is a bystander of injury rather than the direct target.
Prognostic Implications of Troponin Elevation
Regardless of the exact mechanism of cardiac injury, troponin elevation in COVID-19 carries prognostic value in predicting both clinical severity and mortality.7 Risk appears to be continuous with troponin, with worse outcomes predicted by higher elevations.8 Thus, troponins can serve as a valuable marker to triage patients and rightfully have been integrated into several guideline recommendations for management.2
Recognizing the role of critical illness in mediating myocardial injury in COVID-19, Metkus and colleagues further demonstrated that the association between troponin elevation and mortality was attenuated after correcting for degree of critical illness.5 This finding suggests that troponin elevation is unlikely an independent mediator of adverse outcomes in COVID-19 but instead a marker of disease severity and the underlying substrate. Moreover, troponin alone may not be enough to capture clinically meaningful myocardial injury. One imaging study showed that only troponin elevations with concurrent echocardiographic abnormalities were predictive of mortality.9
Role of Cardiac MRI in COVID-19 Myocarditis
CMR has received attention due to early case reports invoking COVID-19 myocarditis. The incidence of COVID-19 myocarditis has proven to be quite low with a recent retrospective multi-center study estimating it to be 1% or less.10 The low pre-test probability of COVID-19 myocarditis should inform appropriate use of CMR to limit exposure risk for patients and personnel. Society guidelines support use of CMR in circumstances where findings have immediate procedural consequences,11 or when evaluating new left ventricular dysfunction or anginal symptoms after coronary disease has been ruled out when the clinical suspicion for myocarditis remains high.12
In resolved infection, emerging studies found inflammation and scar by CMR long after initial diagnosis in up to 60% of survivors in a small Chinese and German cohort13,14 of unknown clinical significance. Moreover, additional comparisons are needed with controls with non-COVID-19 critical illness, as CMR abnormalities have been noted among survivors in other conditions such as sepsis.15
II. Resolved Infection
Return to Play for Athletes
While the role of CMR in the general population is still being refined, athletes have been screened more proactively as a high-risk group due to known associations between myocardial inflammation, exercise-induced arrhythmia, and sudden cardiac death.16
CMR findings in the general population inspired return to play (RTP) algorithms from expert societies to guide US and international sports associations. These guidelines emphasize screening for cardiovascular complications such as myocarditis guided by symptom severity.17 Notably, CMR is generally not recommended as a first-line test but reserved for when abnormalities on initial screening (i.e., electrocardiogram, echocardiogram, or troponin) emerge. If CMR supports the diagnosis of myocarditis, experts recommend following existing American Heart Association (AHA)/American College of Cardiology (ACC) myocarditis guidelines advocating a 3-6-month holiday from sport.
Reassuringly, a recent multi-center cohort study of nearly 800 professional athletes referred for CMR according to ACC RTP guidelines found that the prevalence of myocarditis was only 0.6%, significantly lower than reported from initial single-center studies, with no adverse events occurring among those undergoing screening and returning to play.18
We are learning that the cardiovascular consequences of COVID-19 extend beyond acute infection. Many continue to report lingering cardiopulmonary and neurologic symptoms, namely chronic fatigue, dyspnea, chest pain, and dysautonomia – colloquially known as "long COVID". Of discharged patients, 60-80% reported at least one residual symptom 50 days after initial COVID-19 diagnosis.19,20 Even in non-hospitalized individuals, 35% of those surveyed by the Centers for Disease Control (CDC) reported symptoms 14-21 days after initial diagnosis, even young patients without comorbidities.21
Of particular relevance is a Postural Orthostatic Tachycardia Syndrome (POTS)-like syndrome emerging among COVID-19 survivors. The association between preceding viral illness and POTS has been previously established.22 With ACE2 found on neurons, alteration to the autonomic nervous system has been implicated in COVID-19.23 An increased incidence in POTS will require clinicians to be familiar with current principles in management, which largely center on education, volume and salt optimization, and agents to maintain vascular tone (e.g., midodrine) and manage palpitations (e.g., beta blockers, ivabradine).24,25
COVID-19 impacts the cardiovascular system in both the short and long term. We reviewed here our understanding to date of acute and chronic cardiovascular considerations of infection. The wealth of basic and clinical research spurred by the global pandemic will continue to refine our understanding of the interplay between COVID-19 and the heart in the years to come.
- Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol 2020;5:802-10.
- Bavishi C, Bonow RO, Trivedi V, Abbott JD, Messerli FH, Bhatt DL. Special Article - Acute myocardial injury in patients hospitalized with COVID-19 infection: a review. Prog Cardiovasc Dis 2020;63:682-89.
- Atri D, Siddiqi HK, Lang JP, Nauffal V, Morrow DA, Bohula EA. COVID-19 for the cardiologist: basic virology, epidemiology, cardiac manifestations, and potential therapeutic strategies. JACC Basic Transl Sci 2020;5:518-36.
- Lindner D, Fitzek A, Bräuninger H, et al. Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases. JAMA Cardiol 2020;5:1281-85.
- Metkus TS, Sokoll LJ, Barth AS, et al. Myocardial injury in severe COVID-19 compared with non-COVID-19 acute respiratory distress syndrome. Circulation 2021;143:553-65.
- Guo T, Fan Y, Chen M, et al. Cardiovascular implications of fatal outcomes of patients with Coronavirus Disease 2019 (COVID-19). JAMA Cardiol 2020;5:811-18.
- Sandoval Y, Januzzi JL Jr, Jaffe AS. Cardiac troponin for assessment of myocardial injury in COVID-19: JACC Review Topic of the Week. J Am Coll Cardiol 2020;76:1244-58.
- Lala A, Johnson KW, Januzzi JL, et al. Prevalence and impact of myocardial injury in patients hospitalized with COVID-19 infection. J Am Coll Cardiol 2020;76:533-46.
- Giustino G, Croft LB, Stefanini GG, et al. Characterization of myocardial injury in patients with COVID-19. J Am Coll Cardiol 2020;76:2043-55.
- Laganà N, Cei M, Evangelista I, et al. Suspected myocarditis in patients with COVID-19: a multicenter case series. Medicine (Baltimore) 2021;100:e24552.
- Han Y, Chen T, Bryant J, et al. Society for Cardiovascular Magnetic Resonance (SCMR) guidance for the practice of cardiovascular magnetic resonance during the COVID-19 pandemic. J Cardiovasc Magn Reson 2020;22:26.
- Rudski L, Januzzi JL, Rigolin VH, et al. Multimodality imaging in evaluation of cardiovascular complications in patients with COVID-19: JACC Scientific Expert Panel. J Am Coll Cardiol 2020;76:1345-57.
- Huang L, Zhao P, Tang D, et al. Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging. JACC Cardiovasc Imaging 2020;13:2330-39.
- Puntmann VO, Carerj ML, Wieters I, et al. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from Coronavirus Disease 2019 (COVID-19). JAMA Cardiol 2020;5:1265-73.
- Siddiqui Y, Crouser ED, Raman SV. Nonischemic myocardial changes detected by cardiac magnetic resonance in critical care patients with sepsis. Am J Respir Crit Care Med 2013;188:1037–39.
- Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2018;72:e91-e220.
- Poppas A, Chung EH, Kovacs R. COVID-19 and the athlete: gaining ground but not yet at the finish. J Am Coll Cardiol 2021;77:1368-71.
- Martinez MW, Tucker AM, Bloom OJ, et al. Prevalence of inflammatory heart disease among professional athletes with prior COVID-19 infection who received systematic return-to-play cardiac screening. JAMA Cardiol 2021;Mar 4:[Epub ahead of print].
- Carfì A, Bernabei R, Landi F. Persistent symptoms in patients after acute COVID-19. JAMA 2020;324:603-05.
- Halpin SJ, McIvor C, Whyatt G, et al. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation. J Med Virol 2021;93:1013-22.
- Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network - United States, March-June 2020. MMWR Morb Mortal Wkly Rep 2020;69:993-98.
- Shoenfeld Y, Ryabkova VA, Scheibenbogen C, et al. Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy. Clin Immunol 2020;214:108384.
- Goldstein DS. The possible association between COVID-19 and postural tachycardia syndrome. Heart Rhythm 2021;18:508-09.
- Dani M, Dirksen A, Taraborrelli P, et al. Autonomic dysfunction in 'long COVID': rationale, physiology, and management strategies. Clin Med (Lond) 2021;21:e63-e67.
- Taub PR, Zadourian A, Lo HC, Ormiston CK, Golshan S, Hsu JC. Randomized trial of ivabradine in patients with hyperadrenergic postural orthostatic tachycardia syndrome. J Am Coll Cardiol 2021;77:861-71.
Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Sports and Exercise Cardiology, Atherosclerotic Disease (CAD/PAD), Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Sports and Exercise and Imaging
Keywords: Primary Prevention, COVID-19, SARS-CoV-2, Pandemics, Cardiovascular Diseases, C-Reactive Protein, Benzazepines, Midodrine, Peptidyl-Dipeptidase A, Coronary Artery Disease, Myocarditis, Troponin, Takotsubo Cardiomyopathy, Retrospective Studies, American Heart Association, Cicatrix, Fibrinogen, Myocytes, Cardiac, Triage, Postural Orthostatic Tachycardia Syndrome, Respiratory Distress Syndrome, Critical Illness, Cohort Studies, Oxygen, Patient Discharge, Immunity, Herd, Fatigue Syndrome, Chronic, Multiple Organ Failure, Magnetic Resonance Imaging, Electrocardiography, Arrhythmias, Cardiac, Chest Pain, Echocardiography, Thrombosis, Death, Sudden, Cardiac, Athletes, Dyspnea, Tachycardia, Autonomic Nervous System, Inflammation, Sepsis, Algorithms, Vaccines, Vaccines, Centers for Disease Control and Prevention, U.S., Neurons, Severity of Illness Index
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