Advanced Heart Failure and Transplant

Section Lead:

• Yevgeniy Khariton, MD (@ykmedicine777)

Section Contributors:

• Mohit Pahuja
• Sarah Rosanel, MD (@DrRosanel)

Proposed Mechanisms of Myocardial Injury:

• Cardiotropic mechanisms: COVID19 receptor binding to ACE
• Higher expression in pericytes of ADULT hearts
• Following viral entry, there is
• Suspected down-regulation of ACE2 expression 
• Reduced conversion of Ang-II to Ang 1-7 (protective)
• Virus-mediated lysis of cardiomyocytes
• Robust T cell response exacerbating ventricular dysfunction and injury

(Zhu et al, Curr Cardiol 2020)

(Madjd et al, JAMA, 2020)

(Guo et al, JAHA, 2020)

Incidence of Biopsy Proven COVID19-Mediated Myocarditis:

• Scant biopsy-proven data or autopsy to suggest viral myocarditis 
• Diagnosis is primarily based upon:
• Elevated troponin
• ECG 
• Segmental wall motion abnormalities
• Reduced LVEF/LV wall thickening
• Pericardial effusion 

(Ammirati et al, Int J Cardiol, 2020)

(Tian et al, Mod Pathol, 2020)

Causation versus Association:

• Patients with CV risk factors may already have undiagnosed CMP
• Acute COVID19 may unmask underlying cardiomyopathy

Case Reports:

Case Report 1:

• 53 yo woman without known CV disease 
• ECG: diffuse STE in inferolateral leads with increased troponin 
• Echo w diffuse hypokinesis and LVEF ~40%
• cMR with T2-weighted images met Lake Louise criteria for myocarditis 
• Clinical improvement on medical therapy; serial Echo improved edema

(Inciardi et al, JAMA, 2020)

Case Report 2:

• 67 yo m/w presenting with COVID19 positive-testing and symptoms 
• Echo with large pericardial effusion with signs of global WMA 

JACC: Case Reports (pending full reference; posted on twitter)

Case Report 3:

• 37 yo male with chest pain/dyspnea/diarrhea for 3 days; hypotensive 
• Chest CT with nonspecific lung infection/cardiomegaly/pleural effusion
• ECG with inferior STE; negative angiogram 
• Troponin T > 10.000 ng/L; CK-MB = 12.9 ng/L; BNP = 2,1025 ng/L
• Echo with decrease in systolic function LV dilation/pericardial effusion 
• Concerns for fulminant COVID-mediated myocarditis
• Treatment:
• Methylprednisolone and IVIG 
• Milrinone 
• Broad-spectrum antibiotics 

(Hu et al, Eur Heart J, 2020)

Case Report 4: Takutsubo Cardiomyopathy 

•  58 yo woman with productive cough/fatigue/fever/diarrhea > intubated
• ECG: 1 mm ST elevations in I and aVL; mild diffuse PR depressions
• Troponin peaked at 11.02 ng/mL
• Echo with mid-distal LV hypokinesis and apical ballooning; LVEF 20%
• Treated for ACS with DAPT/heparin 
• Treated with dobutamine due to concerns for cardiogenic shock
• LVEF improvement over days

(Minhas et al, JACC, 2020)

Case Report 1:

• 66 yo male with end-stage ICM post HMII as destination therapy 
• Stable LVAD parameters; intubated for hypoxia and respiratory failure 
• Clinical course complicated by:
• Consideration of PRONING
• Use in LVAD patients has not been well-described
• May increase RV pressures and subsequent RV failure 
• Images of LVAD + plain films included in article
• Key Points:
• Feasibility/benefit of prone positioning in LVAD
• Cellular immunity compromised in MCS ?

(Singh et al, J Card Fail, 2020)

Case Report 2:

• 69 yo patient without significant cardiovascular co-morbidities 
• Treatment with VA ECMO and mechanical ventilation 
• Short-term improvement and recovery of cardiac function over 5-7 days 
• EMB: low-grade myocardial inflammation;viral particles in myocardium 

(Tavazzi et al, Eur J Heart Fail, 2020)

Limited Experience with Use of VV-ECMO:

• In one analysis with 6 patients receiving VV-ECMO, ⅚ died 
• ECMO associated with a reduction of certain lymphocyte populations
• Patients with worse outcomes with lower lymphocyte counts
• Normalized Il-6 level on ECMO shown to be more likely survive MCS
• Should lymphocyte count and Il-6 levels be routinely followed? 

(Henry et al. Lancet Respir Med, 2020)

Larger Center’s Experience with 32 Patients Requiring VV-ECMO:

• 10/32 patient passed away before or shortly after decannulation
• Adjunctive medication management includes: IV steroids, IL-6 receptor 
• Monoclonal antibodies (e.g. Tocilizumab), and hydroxychloroquine 

(Jacobs et al, ASAIO J, 2020)

ECMO Algorithm in COVID19 Setting:

(Keshava et al, Circ Heart F, 2020)

Additional Articles for Review:

https://www.ncbi.nlm.nih.gov/pubmed/32363334.

https://www.ncbi.nlm.nih.gov/pubmed/32364404

https://www-ncbi-nlm-nih-gov.proxy.lib.wayne.edu/pubmed/32358232)

Right Ventricular Longitudinal Strain

• Abnormal RV strain is a potent predictor of COVID mortality

` Ref: (Li et al, JACC:Imaging, 2020)

General Clinical Observations and Patterns

• Clinical presentation and course SIMILAR to non-transplanted population
• Clinical course MAY be attenuated due to immunosuppression

(Webinar: AST Transplantation Town Hall)

Pharmacology and Medication Interactions

• Azithromycin/hydroxychloroquine may require QTc monitoring
• Interactions with calcineurin inhibitors/cyclosporine levels
• Sirolimus AND lopinavir/ritonavir (risk of sirolimus pulm toxicity)
• Lopinavir/ritonavir is a potent CYP3A4 inhibitor
• Lopinavir/ritonavir can increase both tacrolimus and cyclosporine level
• Cyclosporine, tacrolimus, and sirolimus are hepatically metabolized
• ALL may interact with hydroxychloroquine
• Remdesevir is metabolized by the kidneys; adjust for impaired CrCl 

(Ambrosi et al, JHLT, 2020)

*All suspected medication interactions should be discussed and verified by the institution’s own pharmacy department :

Published Case Reports and Other Analyses:

Case Series:

• 28 OHT patients in New York admitted with COVID
• Median time from transplant was 8.6 years
• Medication adjustments:
• Cellcept discontinued in 70%
• Calcineurin inhibitor dose-reduced in 26%
• Treatment included: hydroxychloroquine, steroids, and Il6 antagonists
• Case fatality rate was 25%

(Latif et al, JAMA:Cardiology, 2020)

Case Report 1:

• Patient 5-month post-OHT on MMF/Tacrolimus/Prednisone
• Positive COVID test
• Withdrew MMF
• Tacrolimus dosing adjusted
• Addition of azithromycin and hydroxychloroquine 
• Symptomatic improvement/discharged with ECG monitoring

(Anecdotal Case Report from Italy (Reference: PARAGONIX webinar, below))

Case Report 2:

• 39 yo male with dilated NICM, status post combined heart/kidney
• Remote hx of antibody-mediated graft rejection 
• Positive COVID test > withdrew MMF and prednisone continued
• Initiated on hydroxychloroquine; enrollment in Remdesevir RCT
• Clinical improvement and discharged home

(Hsu et al, American Journal of Transplantation, 2020)

Case Report 3: 

• Unknown age patient, planned for OHT
• Recipient without respiratory symptoms
• Chest CT demonstrated ground-glass findings concerning for COVID
• Lymphopenia on serum testing
• Transplant aborted/deferred

Ref: Anecdotal Case Report from Italy (reference: PARAGONIX webinar, below)

Additional Case Reports:

• 2 post-OHT from Wuhan, China; one with mild disease and other with new severe disease requiring IVIG and steroids; both demonstrated clinical recovery) (Li et al, JHLT, 2020)

Management of Donor Selection and Transplant Harvesting Dilemmas 

Opinion Polling:

Webinar Polling Question:

What is the current approach to the acceptance of medically suitable donors in the setting of COVID19 (opinion consensus during PARAGONIX seminar)?

• Donor chest CT
• Single or multiple negative COVID19 via serum PCR testing
• Antibody testing specific to COVID19
• Negative BAL PCR 

Webinar Polling Question: What would be the most optimal time to transplant a patient on the OHT waitlist, who tests positive for COVID19? (opinion consensus via polling during PARAGONIX seminar)?

• Two negative nasopharyngeal COVID19 with clinical improvement
• Three months after symptom onset and PCR positive status
• Pending positive COVID19 IgG antibodies 

Specific Areas for Consideration During COVID19 Pandemic and Donor:

Selection/Listing:

(Defillipis et al, Circulation, 2019)

(Ai et al., Radiology, 2020)

Ref: PARAGONIX webinar 

Ethics of Cardiac Transplantation in the COVID19 Pandemic:

• Review article from single-center experience (Chen et al, JHLT, 2020)
• ISHLT COVID19 Ethical Statement (Holm et al, JHLT, 2020)

International Experience from England and Italy from PARAGONIX Webinar on Donor and Recipient Screening and Testing Strategies:

• Medical, social, and travel history screening 
• Chest CT screening in symptomatic and asymptomatic patients 
• QT-PCR vs. serology testing 
• Determination of # of tests performed as well as type of specimen

Risk of Donor-Recipient Transmission:

• Insufficient experience to exclude donor-recipient transmission of COVID19 virus
• COVID19 can be detected in
• Blood by PCR
• Stool by PCR and EM
• Kidney by immuno-histochemistry

Recipient Preparation (Experience from England; composite of 5 transplant centers): 

• All patients considered for urgent transplant received COVID19 swab
• All positive patients removed/deferred on wait list 
• Repeat swab performed once patient asymptomatic 
• Prior to transplant, non-contrast CT scan of the chest performed 
• Individualized consent to the potential risk of COVID19 from donor 
• LVAD patients on IV antibiotics 2/2 driveline infection, on urgent

waitlist, discharged on home antibiotics 

• Stable LVAD patients on waiting list deferred on wait list
• All lung transplantation on hold unless recipient is on ECMO support or on urgent waitlist with non-invasive ventilation (e.g cystic fibrosis)
• All patients on temporary MCS therapy (ECMO, BiVAD, IABP) being

considered for urgent transplantation 

• Highly sensitized elective patients considered if matching donor found due to time considerations of location another ideal donor in the future

Donor Preparation (Experience from England; composite of 5 transplant centers) 

• ALL donor patients are treated as “positive,” despite negative

PCR/imaging testing

• Non-contrast CT scan of the chest performed 
• Travel is done with more than 1 vehicle to promote social distancing;

transport vans deep-cleaned after every trip; air travel for only > 2 hours

anticipated road travel

• Full PPE is worn by surgeon and all proximal medical staff during intubation AND sternotomy due to higher risk of aerosolization 
• Surgeon to de-scrub 20 minutes post sternotomy and:
• Change into standard surgical attire
• Marked reduction in particle aerosolization exposure
• Communicate with anesthesia/ICU to reduce ischemia time 

Post-Transplant Care (Experience from England; composite of 5 transplant centers) 

• Post-transplant outpatient visits are strictly telehealth visits 
• Blood samples taken locally and sent to lab via courier system 
• Patients only attend hospital if acutely ill and/or post-OHT EMB/RHC
• All new admissions to hospital are isolated and checked for COVID19
• Standard immunosuppression regimen maintained WITHOUT change

Key Points:

• Organization of transplant team in work shifts 
• Reduce contact between medical trainees and select staff
• Reduce number of transplant surgeons and dedicate them primarily to

transplant

Differentiating Rejection from Myocardial Toxicity in the Post-Transplant Patient:

• Inpatient/outpatient allomap testing has been performed (Ref. Hsu et al. American Journal of Transplantation, 2020)
• Endomyocardial biopsy 

• Other High-Yield References for Donor/Active Listing/Post-Transplant Considerations:

• (DeFillipis et al, Circulation, 2020). (Table at bottom of article)

High-Yield Webinars:

Zoom PaRAGONIX Webinar Reference on Heart Transplantation in a Viral pandemic:

Zoom Meeting 1

Zoom Meeting 2

Hosted UNOS/ISHLT Webinars:

https://unos.org/covid/

AST Transplantation Town Hall