General Cardiology Section

Section Co-Leads:

• Dapo Iluyomade, MD (@DrDapo)
• Issa Kutkut, MD (@ikutkutMD)

Section Contributors: 

• Jasjit Bhinder, MD (@jasjit87)
• Ashish Correa, MD (@ashishcorrea)
• Celso de la Cruz-Luque, MD (@cdlcruzl)
• Nitika Dabas, MD, MPH (@NitikaDabasMD)
• Syed Waqas Haider, MD (@WaqasHaiderMD)
• Kirstin Hesterberg, DO (@theknittingcar1)
• Bernard Kadosh, MD (@BernardKadosh)
• Devika Kir, MD (@DevikaKir)
• Jorge Penalver, MD (@JorgeP15)
• Azar Radfar MSc, PhD, MD (@AzarRadfar)
• Pragya Ranjan, MD (@PragyaRanjan)
• Paniz Vafaei, MD (@PanizVafaei)
• Walid Ibrahim, MD

Virology and Life Cycle

• COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a positive single stranded RNA virus from the betacoronavirus family.
• Zoonotic infection, primary host seems to be chrysanthemum bat, unclear intermediate host (Yuefel et al, Viruses, 2020).
• Among structural proteins, viral surface spike glycoprotein (S protein) is key for entering the host. It uses ACE-2 glycoprotein enzyme as well as transmembrane serine protease 2 (TMPRSS2) to enter the cell and start its replication.
• It attaches first to nasopharyngeal mucosa and then spreads to the lower respiratory tract, as well as viremia.
• Highly abundant in infected patients (up to 1 billion RNA copies/mL sputum). Seems patients who are able to clear the virus in less than 10 days from exposure have better clinical outcomes.
• Stable on surfaces (copper for 4 hours and cardboard/plastic up to 72hrs).
• Primary way of transmission is droplet or direct/indirect contact. Airborne transmission also is possible.

(Source)

ACE-2 Function and Role in Cardiovascular System

• ACE2 is a key negative regulator of the renin-angiotensin system (RAS), has various separate roles including catalytic activities, functional receptor for SARS-CoV, and amino acid transporter linking to COVID-19 immunity, inflammation and multiorgan involvement.
• It cleaves angiotensin I and angiotensin II to angiotensin 1.7 and angiotensin 1.9 with vasodilatory and anti-remodeling properties.
• After binding to ACE-2 expressed in lungs, endothelium, heart and other organs, it seems SARS-CoV-2 downregulates expression of this enzyme, producing enhanced vasoconstriction and deleterious effects of unopposed RAS.
• Non-consistent evidence that ACEi or ARB medications upregulate ACE-2 in an initial phase, which would be beneficial for virus replication. (Gheblawi et al, Circulation, 2020)

Mechanisms of Cardiovascular Injury

• Primary inflammatory response usually seen on early infection (viremia phase)
• Secondary inflammatory response usually seen in late infection (cytokine storm phase)
• Three main mechanism of cardiovascular injury
• Direct viral invasion of myocytes
• Endothelial damage of macro- and micro-vasculature
• ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic

The coronavirus disease 2019 (COVID-19) pandemic began with the identification of a cluster of cases of severe viral pneumonia in the city of Wuhan, in Hubei, China in December 2019. Since then, the causative virus - the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - has spread rapidly to South Korea, Italy and Iran, from where it spread globally. Presently, Western Europe and the United States (US) are the new epicenters of the pandemic. As of April 26 2020, over 2.95 million people had confirmed cases of the infection, resulting in over 205,000 deaths. Over 860,000 people have recovered. 

On January 30 2020, the World Health Organization (WHO) declared the COVID-19 outbreak and spread a “Public Health Emergency of International Concern” and on March 11 2020, it was declared a pandemic. Presently, 225 countries and territories have registered cases of the infection.

Key References:

• Reference 1 (Retrieved April 26, 2020)
• Reference 2 (Retrieved April 26, 2020)
• Reference 3 (Retrieved April 26, 2020)

Mainland China:

Wuhan, Hubei:

• The true extent of known cardiovascular comorbidities and outcomes among patients infected with SARS-CoV-2 in China is not well known, as most studies and reports focused on hospitalized patients.
• Early reports out of China, particularly out of Wuhan, Hubei, showed that known cardiovascular disease was not especially prevalent among people hospitalized with COVID-19.
• Among hospitalized patients, known coronary artery disease (CAD) was seen in 8-11% of patients. (Shi et al.; Zhou et al.)
• The prevalence of diabetes mellitus (DM) was 14-20%, of hypertension (HTN) was 15-31% and of heart failure was 4%. (Huang et al.; Shi et al.; Zhou et al.)
• The prevalence of cardiovascular comorbidities was much greater among those gravely ill; among patients who expired, the prevalence of DM, HTN and CAD was 31%, 48% and 24% respectively. (Shi et al.) Cardiovascular risk factors were found to be independent risk factors of in-hospital death; CAD was associated with over twenty-fold higher odds of death during hospitalization. (Zhou et al.)
• Cardiac biomarker elevation was common among patients hospitalized with COVID-19. High-sensitivity cardiac troponins were found to be elevated in 12-20% of patients. However, troponin elevation was much more among the sickest patients - up to 31% patients requiring intensive care unit (ICU) admission and among 46% patients who expired during their hospitalization. One study found that over half of patients who had elevated troponins died during their hospitalization. Troponin elevatiion closely paralleled clinical deterioration among non-survivors. (Huang et al.; Shi et al.; Zhou et al.)

• One study out of Wuhan found that acute cardiac injury during hospitalization was associated with higher likelihood of supplemental oxygen requirement, mechanical ventilation (non-invasive or invasive), acute kidney injury (AKI), renal replacement therapy and acute respiratory distress syndrome (ARDS). (Shi et al.).

• Known CAD and acute cardiac injury during hospitalization were found to be a risk factors for in-hospital death. (Shi et al.; Zhou et al.)
• Myocardial injury was implicated as a cause of death in many patients. (Ruan et al.)

All Mainland China:

• In a large epidemiological study across mainland China conducted by the Novel Coronavirus Pneumonia Emergency Response Epidemiology Team commissioned by the China Center for Disease Control (CCDC), 72,314 patient records were analysed. Of these, 44,672 (61.8%) were confirmed cases, while 16,186 (22.4%) were suspected cases, 10,567 (14.6%) were clinically diagnosed cases (Hubei Province only), and 889 (1.2%) were asymptomatic cases. Among the confirmed cases, the prevalence of cardiovascular comorbidities was low - HTN 12.3%, DM 5.3% and cardiovascular disease (CVD) 4.2%. However, the prevalence was much higher among patients who died - HTN 39.7%, DM 19.7% and CVD 22.7%. Case fatality rate was elevated among those with these comorbidities - 10.5% for CVD, 7.3% for DM and 6.0% for HTN.
• References:
• The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19) — China, 2020
• Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Outside Mainland China:

Epidemiological information outside mainland China is still sparse, as the pandemic is still on-going with the new epicenters of active cases in the US and Western Europe.

United States:

• As of April 29 2020, there were over 1 million cases of COVID-19 in the US (CDC.gov).
• A report on the prevalence of underlying comorbidities among patients with COVID-19 in the US showed that prevalence of CVD among patients in the US was around 9%. Among non-hospitalized patients, the prevalence was 5%. Among hospitalized patients, the prevalence was 23% among non-ICU patients and among ICU patients, it was 29%. (MMWR)
• In the New York City (NYC) area, the prevalence of CVD among hospitalized patients was somewhat higher than that seen in Wuhan, China. CAD was seen among 11.1% of patients, congestive heart failure (CHF) was seen in 6.9% and HTN was seen in 56.6% of patients. However, similar to that seen in Wuhan, cardiac injury was seen in 22.6% of patients. (Richardson et al.)
• Centers for Disease Control and Prevention. Accessed on April 29 2020
• Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019
• Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area

Rest of the World:

• A retrospective analysis of COVID-19 patients admitted to 72 ICUs in Lombardy, Italy showed that hypertension was very common, being seen in 49% of patients. CVD was seen in 21% of patients, hyperlipidemia in 18% of patients and DM in 17% of patients. Patients with HTN were older and had worse outcomes - 38% of patients HTN died while 22% of patients without HTN died. (Graselli et al)

Myopericarditis

• May result from direct viral infection of myocytes vs amplified host inflammatory response; cardiac biomarkers and ECG abnormalities correlate with increased inflammatory markers.

• Zeng J, et al. 2020 Infection
• Doyen D, et al. 2020 Lancet
• Kim I, et al. 2020. European Heart Journal

Acute Heart Failure and Cardiogenic Shock

• May occur in patients without prior cardiac disease, in heart failure with recovered ejection fractions, myopericarditis, or may only become evident after progressive respiratory dysfunction. Differing recommendations on MCS: consider an option that requires lowest staff support (for example IABP) vs choose ECMO to assist with oxygenation. 

• Tavazzi G, et al. 2020 European Journal of Heart Failure
• Bemtgen X, et al. 2020 ASAIO
• Fried JA., et al., 2020. Circulation
• Paul, JP, et al., 2020 European Heart Journal

Arrhythmias

• Series suggest arrhythmias in up to 16.7% of patients, with rates up to 44% in ICU patients. VT/VF noted to occur in approximately 6%. Atrial Fibrillation noted to occur in 17.7%. Interesting proposed mechanism of VA is that cytokines can directly prolong ventricular action potential duration, directly inhibiting hERG-K + channel.

• Lazzerini PE, et al., 2020 Circulation
• Goyal P, et al., 2020. NEJM
• Kochi AN, et al., 2020
• Chang D, et al. 2020 Heart Rhythm Case Reports
• Wu C, et al. 2020 Heart Rhythm

Acute Coronary Syndromes

• Consider conservative management for stable patients with non-STE ACS. 
• In one case series of patients with ST elevation, 57% of patients with focal ST elevation had reduced EF, whereas 75% of patients with diffuse ST elevation had normal EF. Of the patients who underwent cath, 67% had obstructive coronary artery disease. 
• ESC Guidance for the diagnosis and management of CV diseases during the COVID-19 pandemic
• Bangalore S, et al., 2020. NEJM
• Daniels MJ, et al., 2020. Circulation

Other Articles: 

• Madijd M, et al. 2020. JAMA Cardiology
• Atri D, et al., 2020. JACC: Basic to Translational Science
• Driggin E, et al. 2020. JACC



Cardiac Biomarkers

• Troponin and BNP- myocardial injury as defined by elevated troponin has been associated with worse outcomes including higher mortality. Dynamic changes in both TnT and BNP have been seen in patients who died.
• Single center retrospective case series analyzing 187 patients (Tao et al, 2020)
• 27.8% showed evidence of myocardial injury indicated by elevated Troponin T (TnT) levels. 
• Elevated TnT was associated with worse outcomes.
• Patients with underlying CVD and rising TnT levels had the highest mortality.
• TnT levels significantly correlated with both N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma high sensitivity CRP levels indicating myocardial injury can be closely associated with inflammatory pathogenesis.
• Both TnT and BNP significantly increased in those who died, but no dynamic changes were seen in those who survived. 
• ACC Guidelines on Troponin and BNP use in COVID-19
• Bottom line: Due to nonspecific nature of abnormal troponin or natriuretic peptide, recommendation is to only measure troponin or BNP if acute MI or HF is clinically suspected. Reference.

Electrocardiography

• Cardiovascular complications in the form of ST changes, arrhythmias noted on ECG monitoring.
• No specific ECG changes have been described in patients with SARS-CoV-2 infection. Further, with use of azithromycin and hydroxychloroquine, ECG important for monitoring QTc intervals.
• ACC Ventricular Arrhythmia Risk Due to Hydroxychloroquine-Azithromycin Treatment for COVID-19.

• Giudicessi et al MAYO CLINIC PROCEEDINGS- March 2020.
• Local diagnostic protocols (with dedicated equipment) would need to be developed to ensure a balance between patient care and risk of transmission to other patients and healthcare workers.
• European Society Guidance on Diagnosis and Management of CV Disease during the COVID-19 Pandemic- April 2020.

Echocardiography

• Cardiovascular complications associated with COVID-19, like myocardial infarction, myocarditis and stress cardiomyopathy, can all present with ST-segment elevation on EKG. Discerning the etiology is important for management. Echocardiography, with wall motion abnormalities in coronary vs non-coronary distribution can be helpful in diagnosis and subsequent treatment. 
• In order to limit exposure, local diagnostic protocols need to be developed to limit echocardiograms only to positive patients where it would change management. Moreover, echoes should be focused on the acquisition of images that are essential to answer the clinical question, to reduce patient contact with the machine. 
• American Society of Echocardiography Statement on COVID-19.
• European Society Guidance on Diagnosis and Management of CV Disease during the COVID-19 Pandemic. April 2020.

Cardiac CT

• Recommendations from Society of Cardiovascular Computed Tomography SCCT.
• Incidental lung findings on CT angiography (CTA) should be reported immediately. Note there are a spectrum of findings ranging from normal lung to ARDS.

Guiding points to consider when deciding on the role and timing of CCT

Timing considerations for common indications for CCT amidst COVID-19

(Choi et al. Use of cardiac computed tomography amidst the COVID-19 pandemic)

Cardiac MRI

• Evidence of myocardial edema on T2 weighted imaging, early gadolinium enhancement consistent with hyperemia and late gadolinium enhancement reflective of necrosis/scar aids with the diagnosis of active myocardial inflammation and myocarditis. 
• Also helpful in assessing ventricular function given CMR is the noninvasive gold standard in the quantitative assessment of systolic function.
• Case report of 53 year old otherwise healthy female patient presenting with COVID-19 and acute myocarditis; CMR showing increased wall thickness, biventricular hypokinesis, myocardial interstitial edema, diffuse late gadolinium enhancement and a pericardial effusion consistent with acute myopericarditis

ACEI/ARB 

1. Abrupt withdrawal of RAAS inhibitors in high-risk patients, including those who have heart failure or have had myocardial infarction, may result in clinical instability and adverse health outcomes. (Vaduganathan et al. 2020)
2. Until further data are available, the current recommendations is that RAAS inhibitors should be continued in patients in an otherwise stable condition who are at risk for, being evaluated for, or with COVID-19. (Vaduganathan et al. 2020)

NSAIDS 

1. Some of the most serious complications of COVID-19 are sepsis and cardiovascular or respiratory complications. They occur predominantly in elderly people and those with underlying health conditions. Does use of non-steroidal anti-inflammatory drugs (NSAIDs) increase these risks? We don’t know for certain, but additional risks are plausible on the current balance of evidence. The evidence to date is not strong enough to support advising against all use of NSAIDs, caution is advised. (Little 2020)

Anticoagulation/Antiplatelets

1. The incidence of VTE in COVID-19 patients is not established. Like other medical patients, those with more severe disease, especially if they have additional risk factors (e.g. older, male, obesity, cancer, history of VTE, comorbid diseases, ICU care), have a higher risk of VTE than those with mild or asymptomatic disease. (COVID-19 and VTE)
2. Use LMWH or UFH in hospitalized critically ill patients because of the shorter half-life and fewer drug-drug interactions compared with direct oral anticoagulants. Regular warfarin users who are unable to get INR monitoring during isolation may be candidates for direct oral anticoagulant therapy. Patients with mechanical heart valves, ventricular assist devices, valvular atrial fibrillation, antiphospholipid antibody syndrome, or pregnancy or lactation should continue treatment with warfarin therapy. (COVID-19 and VTE)
3. As per a recent international consensus statement, there is a concern for drug-drug interaction between various investigational COVID-19 therapies and antiplatelet and anticoagulant agents.
4.  Lopinavir/Ritonavir is a CYP3A4 inhibitor and could reduce the effective dose of Clopidogrel and increase the dose of Ticagrelor. It is recommended that these agents be avoided or when available, P2Y12 platelet function testing be used to guide therapy. Alternatively, Prasugrel should be considered instead.
5. Lopinavir/Ritonavir affects the dose of anticoagulants. Dose adjustments are required for vitamin K antagonists, Apixaban and Betrixaban whereas it is recommended that Rivaroxaban and Edoxaban not be co-administered with Lopinavir/Ritonavir.
6.  The authors recommend consideration of VTE prophylaxis in patients that are discharged from the hospital on a case-by-case basis – weighing the thrombotic risk against the hemorrhagic risk. Extended VTE prophylaxis up to 45 days should be considered in patients at highest risk of thrombotic events (e.g. patients with reduced mobility, prior VTE, active cancer, D dimer levels greater than two times the upper limit of normal) and low bleeding risk.
7.  The authors strongly recommend use of DOACS in eligible patients after discharge to limit contact with healthcare providers for the purpose of INR monitoring.
8. They recommend that healthcare systems allocate resources to enable at-home or drive-through INR checks for those patients that are unable to be transitioned to DOAC therapy. (Bikdeli B et al doi: COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up)

Antiplatelet therapy in COVID 19 patients:

1.  With regards to clinical significance, current expert consensus warrants proactive measures or even stopping all antiplatelet therapy in patients with a platelet count < 100,000/μL and < 50,000/μL, respectively. Among patients currently on DAPT, stopping aspirin and maintaining P2Y12 inhibitor monotherapy (preferably ticagrelor) may be scientifically reasonable for patients with PCI performed ≥ 3 months. Due to the lack of convening evidence, for those with PCI performed < 3 months, DAPT should not be discontinued. (Zhou et al. 2020)

Telehealth Considerations

1. Telephone or telehealth visits should be considered for established patients. 
2. Document both encounter types, as you would during an in-person visit. 
3. Telehealth visits for services in the Medicare telehealth program will be reimbursed at in-office rates. 
4. Lead the visit as if the patient is in the room, forgoing the physical exam.

• Bhatt AB, et al. 2020 ACC
• COVID 19 Coding, 2020, ACC
• Schwamm LH, et al. 2020. Circulation
• Coronavirus Waivers & Flexibilities, CMS.gov
• List of telehealth Services, CMS.gov

TTE

1. Identify “non-elective” (urgent/emergent) indications and defer all others.
2. Plan ahead, based on indications, clinical information, laboratory data and other imaging findings to allow for a focused sequence of images that help with management decisions; prepare for use of ultrasound enhancing agent before scanning.
3. Disposable probe covers and forgoing ECG leads may help limit exposure ASE Statement on Protection of Patients and Echocardiography Service Providers During the 2019 Novel Coronavirus Outbreak

TEE

1. TEEs carry a heightened risk of spread of the SARS-CoV-2 since they may provoke aerosolization of a large amount of virus due to coughing or gagging that may result during the examination.
2. TEEs should be postponed or canceled if an alternative imaging modality (e.g. off axis TTE views, ultrasound enhancing agent with TTE) can provide the necessary information.
3. Utilize contrast CT and MRI for left atrial appendage evaluation prior to cardioversion ASE Statement on Protection of Patients and Echocardiography Service Providers During the 2019 Novel Coronavirus Outbreak

CCT

1. CCT may be preferred to TEE in order to rule-out left atrial appendage and intracardiac thrombus prior to cardioversion.
2. The ability of CCT to decisively exclude coronary disease or high risk anatomy may prevent the need for inpatient admissions and resource use.
3. The decision to proceed with coronary CTA versus invasive angiography should be made in collaboration with local clinical staff from the Heart Team, including cardiac catheterization laboratory. It is expected for the vast majority of COVID-19(+) patients, invasive or non-invasive coronary visualization will not change management. SCCT Statement on Use of cardiac computed tomography amidst the COVID-19 pandemic

CMR

1. A diagnostic MRI is not an aerosol-generating procedure, but in a pandemic, all patients should be considered carriers. Healthcare staff needs optimal PPE.
2. Urgent cases only.
3. Careful surface cleaning with extended cleaning protocols for PUIs. SCMR COVID-19 Statement
4. Proposed role for CMR in COVID-19 evaluation. Cardiac MR in the Times of COVID-19

EP

1. Defer elective, non-urgent procedures.
2. For patients with suspected COVID-19, it is optimal to await test results to avoid unnecessary utilization of resources.
3. For patients requiring conscious sedation, which carries risk for aerosolization with high flow oxygen or anesthesia with intubation, proper PPE, including N95 or PAPR masks should be used. Consider elective intubation in the ICU or a negative pressure room prior to entering the EP lab. 
4.  Ensure all needed equipment and supplies are in the room at the start of the case; consider scheduling patients with suspected or confirmed COVID-19 infection as last case of the day.
5. Proposed algorithm from HRS Guidelines. Lakkireddy DJ, et al. 2020. HR

Cardiac Cath Lab

1. Defer elective cases. 
2. Primary PCI should remain the standard of care for definite STEMI; additional time may be required in the ED for COVID-19 testing or additional treatment (ex. respiratory support). For stable patients with STEMI and active COVID-19, fibrinolysis may be considered. 
3. If atypical or not definite STEMI, further testing should be undertaken in the ED, including evaluation of wall motion/ejection fraction. If ECG and TTE findings are discordant, CCTA may be considered. 
4. For patients with NST-E ACS, medical management should be considered unless hemodynamically unstable or high risk features are present. 
5. If rapid COVID-19 testing is not available, any patient presenting to the CCL should be presumed positive. PPE with aerosolized protection for the entire CCL staff should be utilized. Consider PAPR systems, especially for patients who may be vomiting, require CPR or intubation. Cath lab will require a terminal clean following the procedure. 
6. Frederick GP, et al. 2020 JACC
7. Mahmud E, et al. 2020



COVID-19 Pandemic and Cardiovascular Education:

A worldwide pandemic changes the landscape of global healthcare delivery and inline medical and cardiovascular training. It also provokes extraordinary stress on healthcare workers. It is incredibly challenging to balance the emergent requirements of patient care with the maintenance of optimal training, all while promoting staff and trainee safety and well-being.  

Changes in Cardiovascular training as a response to COVID-19 pandemic: 

1. A significant reorganization of inpatient team structure and fellows-in-training (FITs) roles to adapt to rising demand of patient care during the pandemic
2. different conditions from those typically practiced to meet American College of Cardiology (ACC) Core Cardiovascular Training Statement (COCATS 4) and Accreditation Council for Graduate Medical Education (ACGME) Common Program Requirements.

1. The ACGME is allowing institutions to self-declare Pandemic Emergency Status, which allows FITs to function as attending physicians in Internal Medicine; spending up to 20 percent of each academic year (DeFilippis EM, et al. JACC 2020)

1. Elective procedures have been postponed at many medical centers. As a result, general and subspecialty FITs are less exposed to, and experienced in, performing core competencies. A few months without procedural experience may have a significant impact on skill development and achievement of graduation and employment milestones. 

1. ACGME guidance states that if planned curriculum experiences are not completed, program directors and clinical competency committees may adjudicate graduation decisions. (Accreditation Council for Graduate Medical Education. Stage 2: Increased Clinical Demands Guidance 2020).

1. The ACGME advises that a training extension may be necessary if the program director determines that a FIT is not ready for independent practice. (Accreditation Council for Graduate Medical Education. Stage 2: Increased Clinical Demands Guidance 2020).

1. Broad implementation of telemedicine to enforce social distancing and to care for new and established patients.

1. Substituted educational activities with virtual education such as teleconferences, local and national meetings .i.e. ACC 2020, HRS 2020, SCAI 2020

1. The use of social media outlets such as Twitter, Facebook and WhatsApp to share experiences and rapidly disseminate new data/information among trainees

Opportunities for trainees: 

1. Learning about cardiovascular manifestations of COVID-19.
2. Enhanced critical care experience, gained through rotations in cardiovascular intensive care and medical ICU or stepdown units.
3. Practice general internal medicine by caring for primary none cardiac patients. 
4. With patient consent, audio and video telemedicine visits can be recorded on secure platforms, allowing FITs to review, self-evaluate and improve their interpersonal and communication-related competencies.
5. Instant feedback delivery on medical history taking and decision-making after joint telemedicine visits.