INTRODUCTION

Cardiac imaging is indispensable in the spectrum of management in heart failure (HF) patients and orthotropic heart transplant (OHT) recipients, from diagnosis and risk-stratification to treatment initiation and surveillance. Advanced techniques can detect subclinical dysfunction by demonstrating abnormalities at the level of myocardial tissue and capillary perfusion. In turn, they may facilitate superior prognostication, and improve our understanding of heart failure (HF) etiology and mechanisms of disease.

During this COVID-19 pandemic, efforts to protect healthcare workers and curb the spread of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) are grounded on judicious resource utilization in both the inpatient and outpatient settings. The inevitable disruption of care to established HF patients may have unforeseen long-term consequences.¹ Acute cardiac injury is seen in up to 17% of COVID-19 patients and is a significant contributor to morbidity and non-survival. At least two cases of OHT recipients contracting COVID-19 have been reported, with favorable outcomes after modulating immunosuppression.²

We review modified indications for cardiac imaging during the COVID-19 pandemic and offer a thoughtful approach toward resource utilization, while maintaining a safe environment for patients and providers. Areas of concern are highlighted, with strategies to mitigate exposure, particularly in patients with left ventricular assist devices (LVAD) and OHT recipients.

ECHOCARDIOGRAPHY

Echocardiography is the foundational modality in assessing cardiac structure and function. It is widely available, portable, non-toxic, reproducible, and relatively inexpensive. Advances in echocardiography include the ability to detect subclinical dysfunction and differentiate between patterns of disease with strain analysis. In addition, 3-dimensional echocardiography (3DE) has shown improvements in accuracy for assessment of biventricular volumes and systolic function.^3,4 Ultrasound-enhancing agents (UEA) are widely used to improve endocardial definition. They may also be used as perfusion agents to distinguish hibernating myocardium from scar, providing viability assessment. Studies show both contrasted 3DE and 2DE studies demonstrate superior accuracy in measuring volumes and systolic function over non-contrasted studies, comparing against the gold standard of cardiac magnetic resonance imaging (CMR).⁵

Hemodynamic assessment, filling pressures, stroke volume and cardiac output can be calculated with conventional 2DE and most cardiac point-of-care-ultrasound (POCUS) machines – a common fixture in most intensive care units (ICU). Assessing hemodynamics with 2DE may offset the need for invasive cardiac monitoring with a pulmonary artery catheter.

The most significant limitation to echocardiography is poor acoustic windows from any cause, which can largely be overcome by using UEA. Image quality remains heavily dependent on operator performance. Lastly, echocardiography is unable to illustrate morphologic changes at the tissue or cellular level; this may change in the future with further advances in strain imaging and perfusion techniques.

Stress echocardiography (SE) assesses many aspects of cardiac function in response to an increasing workload. Examples include ischemia evaluation, viability, diastolic function, valvular disease, pulmonary hypertension, and the hemodynamics of hypertrophic cardiomyopathy. SE can be performed with exercise (treadmill or bicycle) or pharmacologic agents, of which, dobutamine is the most commonly used. In addition to improving wall motion assessment, using UEA for perfusion imaging during pharmacologic SE can augment detection of ischemia and offer viability assessment.⁶

Recommendations for performing SE during the COVID-19 pandemic include protective measures for staff members and patients, and avoiding exercise studies, particularly if a non-exercise modality will yield the same information. In addition, exams performed on patients in isolation should be carefully planned based on clinical indication and prior imaging to reduce exposure time and use of personal protective equipment (PPE). UEA use should be anticipated and brought into the room initially to avoid exposure while waiting for them to be procured. Transesophageal echocardiograms (TEE) should be carefully screened and strict PPE protocols maintained when performing studies in COVID patients due to droplet transmission and aerosolization risk. Lastly, frontline clinicians treating COVID patients, who are proficient in cardiac POCUS, should perform as many studies as possible and coordinate with the echocardiography laboratory for reporting.⁷

NUCLEAR IMAGING

Radionuclide myocardial perfusion imaging (rMPI) is a widely used modality for ischemia evaluation. Two main rMPI camera systems are used: single-photon emission computed tomography (SPECT) or positron emission tomography (PET). Cardiac function and perfusion are assessed at rest and at peak stress with either exercise or pharmacologic stress. Pharmacological agents include vasodilators and inotropes. Regadenoson, a vasodilator, is the most commonly used. Advantages of PET include superior image quality, lower radiation doses, myocardial viability information, and quantitative assessment of coronary flow reserve (a measure of microvascular function). Additionally, electrocardiogram (ECG)-gated studies will provide an ejection fraction and left ventricular (LV) volumes.^3,4,8

An abridged stress-only single-photon emission computerized tomography (SPECT) protocol is available with 99m-technitium-labelled radioisotopes. The stress portion is performed first, and if results are unequivocally normal, rest imaging is not needed. Patient selection is key, and relative contraindications include prior abnormal rMPI, weight >300 lb, known cardiomyopathy and known severe coronary artery disease (CAD) without prior revascularization, which are well known limitations of SPECT imaging. Accordingly, PET is preferred in patients with high body mass index (BMI), severely reduced systolic function, and with complex CAD.^9,10

Advanced rMPI protocols for myocardial viability and inflammation are helpful in risk stratifying patients with complex coronary artery disease and detecting acute inflammation in patients with equivocal CMR results, respectively. A judicious approach to these modalities should be taken, with the intent to maximize information yield with any one study and minimize the overall number of studies. For example, a well-planned pharmacologic PET perfusion and metabolism protocol will yield both ischemia and viability information with one study.¹⁰

Myocardial Viability: for patients in whom myocardial viability information will strongly influence management, a combination PET study for myocardial perfusion and metabolism is strongly recommended. Myocardial metabolic activity, and therefore viability, is provided by adding the radiotracer, ¹⁸F-fluoro-2-deoxyglucose (¹⁸F-FDG). Areas of diminished blood flow from the perfusion study in the presence of metabolic activity correspond with hibernating myocardium. Viability testing can be considered in patients that are hospitalized that need urgent revascularization. For routine planning purposes, testing should be deferred during COVID-19.^9,10

Myocardial Inflammation: ¹⁸F-FDG can also highlight metabolic activity relating to myocardial inflammation. In myocarditis, inflammatory cell infiltration and activity are highlighted with ¹⁸F-FDG uptake, as normal cardiomyocytes preferentially use fatty acid oxidation for energy. Areas with abnormal metabolism are compared to rest perfusion images to delineate inflammation, scar, and normal myocardial metabolism. ¹⁸F-FDG-PET imaging is useful in the diagnosis and treatment surveillance of inflammatory cardiomyopathies, most commonly cardiac sarcoidosis. In the era of COVID-19, unless the results will immediately guide a change in immunosuppression, consider deferring inflammation studies until risk is lower.¹⁰

Device/Prosthesis Infection: ¹⁸F-FDG labeling of inflammatory cells at the site of an infection is gaining use in detecting infections in implanted devices and prosthetic valves. Of note, specificity is poor in the early post-procedural period due to expected inflammatory reactivity at the implantation site. Data are lacking for identifying LVAD-related infections. Small vegetations may be missed. Overall, ¹⁸F-FDG PET imaging may be considered as an alternative to TEE for endocarditis diagnosis and treatment surveillance in carefully selected patients with a high pretest probability.¹⁰

The overall limitations of nuclear testing include high cost, long-duration for studies, multi-acquisition protocols, radiation exposure, and lower resolution than other modalities such as CMR or echocardiography. The long duration of studies alone warrants careful screening in patients with active COVID-19 infection to minimize exposure and preserve PPE.

In accordance with the recent guidelines from the American Society of Nuclear Cardiology (ASNC) and Society of Nuclear Medicine and Molecular Imaging (SNMMI), recommendations specific to the COVID-19 pandemic include prioritizing tests that will impact acute management, delaying other tests, avoiding exercise protocols and careful patient selection for abridged stress-only protocols.¹¹ Lastly, given the fluctuating number of daily studies, communicating with the nuclear medicine staff at least 24 hours in advance may help guarantee radioisotope availability.

CARDIAC MAGNETIC RESONANCE IMAGING

CMR imaging provides accurate assessments of cardiac anatomy, function, and noninvasive tissue characterization. It offers valuable insights into the diagnosis and prognosis of ischemic disease, myocarditis, and inflammatory/infiltrative cardiomyopathies such as hypertrophic cardiomyopathy, sarcoidosis, and amyloidosis. Late gadolinium enhancement (LGE), the pillar of CMR imaging, quantitates myocardial fibrosis and LGE distribution patterns are helpful in establishing an etiology. LGE is limited in the setting of diffuse myocardial fibrosis and acute edema. Additional techniques such as native T1-mapping, extracellular volume mapping, T2-weighted imaging, and early gadolinium enhancement (EGE) may help overcome these limitations.

Advantages of CMR include non-ionizing modality, highly favorable spatial and temporal resolution, and less operator-dependence than echocardiography. Acquisition of 3D data sets makes CMR uniquely well-suited for evaluating the complex anatomy in congenital heart disease. CMR can distinguish between ischemic and non-ischemic cardiomyopathy and provide, particularly in infiltrative cardiomyopathies.^3,4,12,13

Ischemia Evaluation/Myocardial Viability: CMR can delineate normal myocardium, hibernating myocardium, and myocardial fibrosis. In addition, prognostic information is obtained through viability assessment and scar quantification.

Similar to PET, during the COVID-19 pandemic, CMR viability should only be pursued in hospitalized, unstable patients to guide urgent revascularization. Testing should be deferred for routine planning purposes.

Myocardial Fibrosis/Inflammation: combining several CMR techniques have improved detection of acute myocarditis and fibrosis. The Lake Louise criteria can be especially helpful in identifying myocarditis and employs T2-weighted imaging, LGE and EGE.¹² With the overlap between CMR and PET, judicious selection of the study yielding the most information is recommended.

In many instances, the urgency for CMR can be delayed as it will often not impact immediate management. One exception for this is for patients with acute myocarditis, in whom CMR may guide initiation of immunosuppression.¹⁴ Although data is limited, use of CMR to gain insights into the cause of cardiomyopathy with COVID-19 may be helpful. Risk/benefit must be considered due to risk for exposure.¹⁵

Disadvantages include long-duration of studies, need for patient breath-holding and interference from cardiovascular implantable electronic devices (CIED) and other implants. Most CIEDs are MRI compatible, but coil artifact remains a significant problem. Coronary stents and mechanical valves are not contraindications for CMR studies.¹⁶ The risk of nephrogenic systemic fibrosis precludes gadolinium administration in patients with estimated glomerular filtration rate <30 mL/min. Lastly, the spatial resolution is not as high as CT and assessment of smaller structures, such as coronary arteries, is limited.^12,13

LEFT VENTRICULAR ASSIST DEVICES

Echocardiography is indispensable in the longitudinal care of patients with LVADs. It aids in speed optimization based on geometric and functional parameters such as ventricular septal alignment, mitral regurgitation severity, right ventricular (RV) function, and aortic valve (AV) opening. Additionally, it has a key role in suspected RV failure, pump thrombosis, inflow, and outflow graft obstruction and LVAD dysfunction.¹⁷

Non-contrasted cardiac computed tomography (CCT) in LVAD patients is ancillary to echocardiography and aids in visualizing areas obscured on echocardiography, such as the outflow cannula. CCT is useful in detecting post-surgical complications, including large vessel injury, mediastinal and pericardial fluid collections, and thrombus evaluation. In patients with suspected RV failure and challenging echocardiographic windows, CCT is an excellent modality for accurate assessment of RV ejection fraction and volumes. This requires ECG-gating and intravenous contrast administration.^18,19 There is no established role for routine rMPI imaging in LVAD patients. CMR is contraindicated in patients with LVADs.

During COVID-19, it may be reasonable to defer routine LVAD optimization for patients that remain clinically stable. For cases of RV failure, pump thrombosis and LVAD dysfunction, an echo should still be performed, and CCT may be indicated to examine the canulae.

HEART TRANSPLANTATION

Echocardiography is fundamental in the continuum of patient care after OHT. Immediate post-transplant studies are typically requested to evaluate biventricular function or to detect pericardial effusion. Long term, echocardiography is routinely used to follow graft function and is the recommended first test when graft dysfunction is suspected. Endomyocardial biopsy remains the standard for confirmation.^20,21

Coronary allograft vasculopathy (CAV) is characterized by homogenous smooth narrowing of the arteries, typically resulting in a balanced reduction of global perfusion. Dobutamine stress echocardiography (DSE) is routinely used for CAV screening and surveillance following OHT. DSE offers both diagnosis and prognostication; worsening function on serial DSE is associated with increased risk of adverse outcomes. DSE has adequate specificity but poor sensitivity in diagnosing CAV due to the high prevalence of balanced ischemia.²¹ SPECT is further limited in this regard. Perfusion analysis by PET for myocardial flow reserve is an excellent alternative to DSE and is superior to SPECT for CAV evaluation.²¹

In the era of COVID-19, DSE should only be pursued in urgent scenarios where it will change management. Routine functional assessment for the stable patient should be deferred until the risk of COVID-19 exposure is lower. Routine CAV screening in low-risk patients should be deferred for as long as possible. In symptomatic patients at intermediate risk, DSE should be considered, with PET as a preferred alternative. High-risk patients should proceed to coronary angiography.

For the OHT recipient with active COVID-19 infection, a screening echo, particularly POCUS, is strongly recommended to evaluate graft function. Data are limited but there is appropriate concern for graft dysfunction from active infection and/or inflammation.^22,23 The impact of chronic immunosuppression in OHT recipients exposed to or infected with SARS-CoV-2 is unclear. Despite the increased risk for infection, patients may not mount the hyper-inflammation response seen in some severe cases of COVID-19.²⁴

SUMMARY

Considerations for cardiac imaging in the COVID-19 era include thoughtful patient and study selection with a goal to limit the overall number of tests. Key points from respective society guidelines are summarized in Table 1. General recommendations are as follows:

• Defer routine or low-risk studies that are unlikely to change short-term management
• Ensure proper PPE during exercise protocols and TEE (if they cannot be avoided)
• Judicious study selection to maximize information yield using the fewest tests
• Advanced discussion with imaging staff to minimize repetitions and optimize study protocols

Lastly, an opportunity to improve patient care is evident when considering reports of late presentation of acute coronary syndrome, stroke, and other illnesses. Proactive outreach efforts are paramount in addressing the widespread uncertainty around obtaining medical care for non-COVID related reasons. We must reinforce patient education on when to seek medical attention and emphasize the available pathways at respective institutions.¹

Table 1: Selected recommendations from the American Society of Echocardiography (ASE), American Society of Nuclear Cardiology (ASNC), Society for Cardiovascular Magnetic Resonance (SCMR), Society of Cardiovascular Computed Tomography (SCCT).^7,11,15,25

General Recommendations	Echocardiography	Nuclear Imaging	Cardiac MRI	Cardiac CT
Ascertain COVID status prior to procedure as feasible Ensure proper PPE during exercise protocols and TEE (if they cannot be avoided) Delay elective, low-risk testing for routine surveillance Defer studies that are unlikely to change short term management Judicious study selection to maximize information yield using the fewest tests Advanced discussion with imaging staff to avoid repetitions and optimize study protocols	Routine use of ultrasound-enhancing agents (UEA) to increase study yield Planned use of POCUS by frontline providers in COVID patients and  coordination with the echocardiography laboratory for reporting Judicious use of TEE given droplet transmission and aerosolization risk	Utilize the stress-only SPECT protocol in selected patients with a high pretest probability of a normal study 18F-FDG-PET stress testing can provide ischemia evaluation, LV function and volume, and viability in one test, potentially balancing its high cost In native and device-related intracardiac infection, 18F-FDG-PET is an alternative to TEE for diagnosis and treatment surveillance Defer 18F-FDG-PET confirmatory studies for myocardial inflammation, unless results will immediately impact immunosuppressive therapy Advanced discussion with nuclear medicine staff can help ensure isotope availability	CMR stress testing can provide ischemia evaluation, viability information and superior characterization of cardiac anatomy and function with one test Test of choice for acute myocarditis evaluation, particularly to guide initiation of immunosuppression Test of choice for high-risk cardiac masses for surgical planning Test of choice for pericardial constriction evaluation for urgent surgical planning Preferred alternative to TEE for cardiac thrombus evaluation	Supplementary to echocardiography in LVAD patients with suspected RV failure, LVAD dysfunction, and cannula malposition Test of choice in LVAD patients with suspected post-surgical complications Preferred alternative to TEE for cardiac thrombus evaluation Preferred modality in aortic dissection assessment

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Clinical Topics: COVID-19 Hub, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Structural Heart Disease, Angiography, Echocardiography/Ultrasound, Nuclear Imaging, Mitral Regurgitation

Keywords: Heart Failure, COVID-19, Myocardial Perfusion Imaging, Dobutamine, Fluorodeoxyglucose F18, Echocardiography, Stress, Body Mass Index, Coronary Artery Disease, Stroke Volume, Myocarditis, Myocytes, Cardiac, Cicatrix, Point-of-Care Systems, Vasodilator Agents, Patient Selection, Gadolinium, Nephrogenic Fibrosing Dermopathy, Coronary Angiography, Aortic Valve, Nuclear Medicine, Mitral Valve Insufficiency, Prognosis, Breath Holding, Coronary Vessels

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