COVID-19 and cardiovascular complications

What we know so far & how to be prepared

June Rhee, Han Zhu, Paul Cheng, and Sean Wu @ Stanford CV med

Photograph: AP

Outline

• Brief biology of COVID-19

• Overall epidemiology & spectrum of cardiac complications related to COVID-19

• Cardiac complications• Myocardial injury• Pulmonary hypertension and RV failure• Arrythmia and cardiac arrest

• Current available/experimental treatment options and cardiotoxicities

• ACEI/ARB considerations

• Q&A with Drs. Bill Fearon, Patricia Nguyen, Connor O'brien, Mohan Viswanathan, and Ron Witteles

Disclaimer

1. We have not directly cared for patients with COVID-19

2. Some of the information/data/cases have been obtained from bioRxiv/medRxiv + other online resources that are pre-printed/not peer-reviewed

https://pages.semanticscholar.org/coronavirus-research

COVID-19 – Once In A Lifetime Pandemic

Stock Market

Slide From @Xihong_Lin at Harvard Biostatistics Dept

Supermarket

City Streets

Origin of COVID-19

Slide From @Xihong_Lin at Harvard Biostatistics Dept

Population size: 11M

Dec 8, 2019:

First case

Jan 11, 2020:

Spring Festival

Travel 500K ppl

Jan 23, 2020:

Shelter-in-Place

& Lock Down

Feb 2, 2020: 2

New & 16 Field

Hosp Launched

Closed on Jan 1st, 2020

Basics of SARS-CoV-2

Enveloped + sense ssRNA virus

Genome sequence suggest bat-derived source

96% identical in nucleotide sequence to SARS-CoV, the cause of SARS in 2003

Slide Courtesy of Greater Boston Consortium of Pathogen Readiness Symposium

Lung Epithelial Cells (Type II Pneumocyte)

ACE2

Clinical Manifestations of COVID-19

Slide Courtesy of Greater Boston Consortium of Pathogen Readiness Symposium

Munster V NEJM Feb 20, 2020; Zhou F Lancet Mar 9 2020; Guan W NEJM Feb 28 2020

Clinical context• The overall case fatality rate (CFR) of COVID-19 based on published reports remains low at 3-4%

• CFR varies widely: Italy 7.2%, China 3.5%, Iran 2.7%, 2.7% Iran, <1% cruise ship and 0.5% South Korea(worldwide 4.24%).

• More than 80% of infected patients experience mild symptoms and recover without intensivemedical intervention.• In the case of Diamond Princess: 46.5% asymptomatic at the time of testing

ACC COVID-19 Clinical Guidance For the Cardiovascular Care Team & CDC

• COVID-19 cases are rapidly rising in the US

• As of March 24, 2020: there are 54,453 cases + 737 deaths (1.4% CFR)

Flu & COVID-19 death rates by age

Elderly patients are particularly vulnerable!

Onlder G et al. JAMA 2020

0 0 0.3 0.41

3.5

12.8

20.2

0

3

6

9

12

15

18

21

10-1

9

20-2

9

30-3

9

40-4

9

50-5

9

60-6

9

70-7

9

80+

Causes of COVID-19 associated death

• Cardiac complications are the leading cause of death following respiratory failure

• Patients with underlying cardiovascular disease are at higher risk of contracting COVID-19 and have a worse prognosis

Case fatality rates for comorbid patients are materially higher than the average population:• Cancer: 5.6%• Hypertension: 6.0%• Chronic respiratory disease: 6.3%• Diabetes: 7.3%• Cardiovascular disease: 10.5%

Lancet 2020, Zhou et al

CVD comorbidities may increase risk for contracting COVID-19 and portend worse outcome

JAMA. 2020 Feb 7. doi: 10.1001/jama.2020.1 Wang D et al.Lancet. 2020;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Chen N. et al.

High burden of underlying CVD in patients with COVID19 (China)

ICU No-ICU

High burden of underlying CVD among critical ill COVID-19 patients (China)

Acute cardiac complications of COVID-19

• Published and anecdotal reports indicate COVID-19 related cases of:• Myocardial injury + cardiac dysfunction

• Direct myocardial insult?

• myocarditis

• myocardial infarction vs microvascular events

• stress CM

• pulmonary hypertension and RV dysfunction

• arrhythmia, cardiac arrest

• Cardiac complications of COVID-19 are approximately commensurate with SARS, MERS, and influenza analogs

Modified from ACC COVID-19 Clinical Guidance For the Cardiovascular Care Team

Cardiac injury portends worse outcomes

Case #1: 37 yo M with CP & Dyspnea x 3 days

•Admitted on Jan 14, 2020 with 3 days chest pain, dyspnea, and diarrhea

•Hypotensive with BP 80/50 mmHg

Hu H et al. Eur Heart J. 2020. doi: 10.1093/eurheartj/ehaa190.

Case #1: 37 yo M with CP & Dyspnea x 3 days

• Troponin T > 10,000 ng/L

• CKMB elevated at 112.9 ng/L

• NT-proBNP 21,025 ng/L

• Sputum positive for SARS-CoV-2 (negative for extensive viral panel)

• CT coronary angiogram: no obstructive CAD

• Echo:• Enlarged LV with markedly decreased LV systolic function. Estimated LVEF of

27%

• Trace pericardial effusion

Hu H et al. Eur Heart J. 2020. doi: 10.1093/eurheartj/ehaa190.

Case #1: 37 yo M with CP & Dyspnea x 3 days

• Diagnosed with myocarditis with cardiogenic shock in the setting of pulmonary infection

• Treated with methylprednisolone 200 mg/day for 4 days

• IVIG 20 g/day for 4 days

• Pressors, diuretics, zosyn (presumed bacterial superinfection)

• Biomarkers improved over course of 1 week

• No biopsy or other imaging study to confirm active myocardial inflammation

Hu H et al. Eur Heart J. 2020. doi: 10.1093/eurheartj/ehaa190.

Hypotheses of Cardiac Injury

Case #2: 74 yo M presenting after 7 days cough/dyspnea

•7-10 days of cough, fever, shortness of breath

• 1 week PTA: urgent care -> clean CXR

• ED: sat 80's RA, otherwise VSS -> intubated

• EKG: RBBB, no ischemic ST or T wave changes

• COVID status: positive

• Labs on admission: Trop 0.04, WBC wnl, lactate 3's, Cr/LFTs wnl, CRP >30

• Day 6: Pressor requirement, repeat TTE: marked to severe RV dysfunction; RVSP = 71 mmHg

CXR: multi-focal bilateral pulmonary infiltrates

Disclaimer: this case is modeled after an actual case

Pulmonary HTN & RV Failure

• Etiology of pulmonary HTN & RV failure: explained fully by ARDS?

• Early reports from Korea/China, observed pulmonary HTN possibly out of proportion to the observed lung injury with subsequent RV strain + troponin elevation

• Wuhan data: case reports of microthrombi in pulmonary vasculature on autopsy (Luo et al, Preprints, 2020) , as well as classic pulmonary emboli (Xie et al, Radiology: Cardiothoracic Imaging, 2020)

Xie et al, Radiology: Cardiothoracic Imaging, 2020

Is there Increased Risk of Arrhythmia with SARS-CoV-2 Infections?

ACC Updates Suggest Possible Increased Arrhythmia in COVID-19 patients

Major Caveat: Exact arrhythmia not defined in the JAMA study.

JAMA 2020, Wang et al

Increased Arrhythmia Not Observed in Other Studies

• Clinical Characteristics of Coronavirus Disease 2019 in China (Guen et al, NEJM 2020)• 51 centers, 1099 patients, no reported incidence of arrhythmia

• Epidemiological and clinical features of 2019-nCoV acute respiratory disease casesin Chongqing municipality, China: a retrospective, descriptive, multiple-center study. (Qi et al, Medrixv)• 267 pt, 3/50 severe pt had trop >0.03, no arrhythmia reported

• Clinical and radiographic features of cardiac injury in patients with 2019 novel coronavirus pneumonia (hui et al, medrxiv) (Beijing)• 2/3 (total) ICU patient had afib (one with known diagnosis. Mean age of these two pts 75… )

• Clinical features and outcomes of 2019 novel coronavirus-infected patients with cardiac injury (41 pts) (Liu et al, medrxiv ) (Guangzhou)• 5 % with trop > 0.03 (15/291), no arrhythmia reported

Summary of COVID-19 cardiac complications

• Patients with underlying CVD have overall poor prognosis

• Patients who suffer from myocardial injury have overall worse outcome

• Potential cardiovascular complications include:• myocardial injury and cardiac dysfunction

• Direct myocardial insult

• myocarditis

• myocardial infarction vs microvascular events

• stress CM

• pulmonary hypertension and RV dysfunction

• Possible arrhythmia, cardiac arrest

Are there any treatments?

Hypothesis of Viral Pathogenesis & Immune Response

Siddiqi, Journal of Heart & Lung Transplantation, 2020

Viral Load as a Main Determinant of Disease Severity in Acute Phase

Potential treatments: Remdesivir (Gilead)• Designed to inhibit Ebola RNA-dependent RNA polymerase (RdRp).

• Works against SARS-CoV-2 in cells.

• First use in the US patient reported good response without significant side effects (NEJM 2020 Holshue ML et al.)

• Thus far, dosed to >11 US patients on compassionate basis, with good anecdotal results

• In randomized controlled trials in China (data due mid-April) and also in US sponsored by NIAID• https://clinicaltrials.gov/ct2/show/NCT04280705

• No known cardiovascular toxicities thus far, given paucity of data available

Slide courtesy of Dr. Michael Lin (modified)

Wang M et al. Cell Res. 2020 30(3):269-271. doi:

10.1038/s41422-020-0282-0.

How about Lopinavir-Ritonavir?

Potential treatments: Chloroquine

• Generally used for treatment of malaria and amebiasis.

• Has anti-viral activity in vitro and in vivo, but no clinical data to support anti-viral therapy.

• Thought to work via multiple mechanisms but the exact mechanism remains unknown

• Potential cardiotoxicities:

• QT prolongation (“Quinidine effects”) + cardiac arrest: increasing risk of torsades de pointes

• Cardiac dysfunction (has negative inotropic effects)

• Possible conduction abnormalities when overdosed

Wang M et al. Cell Res. 2020 30(3):269-271.

doi: 10.1038/s41422-020-0282-0.

Potential treatments: immunomodulators

COVID-19 and cytokine storm?

Premise:

• Prominent lymphopenia, with normal WBC count

• Degree of lymphopenia correlating with severity

• Acute multi-organ failure with high fevers mimic those seen in drug-induced cytokine storm

Hypothesis:

• “Cytokine storm” induced by the virus contribute to the impaired immune response, and hyper-inflammation is part of pathogenesis

IL-6 Level Correlate with Disease Severity Better than other Inflammatory Markers

• Anecdotal effective treatment with Tocilizumab from Italy and China

• Current ongoing trial for IL-6 blockade in COVID19 pts

• NCT04315298 (New York , Sarilumab)

• ChiCTR2000029765 (Hubei, China, Tocilizumab)

Tocilizumab Treatment With Some Promise

ChinaRxiv, unpublished

• 21 consecutive "severe" patient

• 19 discharged from hospital with "rapid improvement."

Additional ImmunomodulatorsGlucocorticoids IVIG Convalescent

Plasma

• Suppress inflammatory cytokines

• Delayed viral clearance; WHO recommends advises against for Sars-CoV-2 ARDS unless another indication

• Phase 2 RCT: Solumedrol 40 mg q12h for 5 days in ICU level pts w/ PaO2/FiO2 < 200 mmHg (NCT04244591)

• Complement activation; saturation of Fc receptors on macrophages; and suppression of cytokines/chemokines

• Good safety profile, benefit in MERs & SARS

• Phase 2 RCT: IVIG 0.5g/kg/d for 5 days in pts w/ PaO2/FiO2 < 200 mmHg and/or multi-organ failure (NCT04261426)

• Plasma of recovered donors (protective antibodies)

• Donors: recovered patients > 14 days; females HLA Ab neg; male donors

• FDA expanded access for respiratory failure or shock

Summary of COVID-19 treatments

Concerns Regarding ACE/ARB Use During COVID-19 Outbreak

J Virol. 2014;88(2):1293-307. doi: 10.1128/JVI.02202-13.

“Upon binding of virion-associated SARS-S to ACE2,virions are taken up into endosomes, where SARS-S iscleaved and activated by the pH-dependent cysteineprotease cathepsin L. “

•ACEI may lead to decreased Ang II level, increasing interactionbetween ACE2 and AT1 receptor, and preventing ACE2internalization, degradation.•AT1 receptor antagonism with losartan also increase ACE2level by preventing ACE2 internalization/degradation.Source: http://www.nephjc.com/news/covidace2

Concerns Regarding ACE/ARB Use During COVID-19 Out Break

AHA/ACC/HFSA Joint Statement

What we need

ACC COVID-19 Clinical Guidance For the Cardiovascular Care Team

CV-specific plans in collaboration with hospital-wide infectious disease response plans and other medical specialties (e.g. specific protocol for managing AMI in the context of a COVID-19)

Social distancing + isolation!

Key lessons from Chinese experience:

◦ Lockdown with mitigation (1/23)

◦ Centralized quarantine (2/1)

◦ Frontline health care worker housing

R=3.88

R=1.25

R=0.32

Are we flattening the curve?Are we flattening the curve?

Q&Awith

Bill FearonPatricia NguyenConnor O'brien

Mohan ViswanathanRon Witteles

Question #1:

• What are some special considerations in management of STEMI in COVID-19 patients?

Question #2:

• What imaging modalities would use in cases of COVID-19 related cardiac injury/dysfunction?

Question #3:

• How would you approach COVID-19 related new onset LV dysfunction?

Question #4:

• What are some special considerations in management of arrhythmia in COVID-19 patients? Would you give amiodarone?

Question #5:

• What are some special considerations in managing COVID-19 patients under ventilatory support + cardiac complications?

Thank you!