Leslie T. Cooper, Jr., MD

Myocarditis and Heart Failure: Diagnosis, Prognosis and

Treatment

24th Annual Heart Failure 2020:

an Update on Therapy

August 1st, 2020

DISCLOSURE

Relevant Financial Relationship(s)

None

Off Label Usage

None

Outline

• Viral or Lymphocytic Myocarditis-

New definitions, diagnosis and management

• Giant Cell, Hypersensitivity, and Checkpoint

inhibitor myocarditis, Cardiac Sarcoidosis

Bozkurt, B et al Circulation 2016 Caforio, EHJ 2013

Myocarditis and Cardiomyopathy # Deaths and Death Rate /100,000

1990-2015

JACC, Nov 29th 2016

Lancet November 10th, 2018

1.37M myocarditis cases in 2019

343,000

Myocarditis Clinical Presentations

• Myopericarditis/MINOCA

• Sudden Death

• Acute Dilated Cardiomyopathy

• Chronic Dilated Cardiomyopathy

Acute Myocarditis EKG

CP1291921-1

I

II

III

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

QRS > 120ms, high degree heart block

Predict poor outcome

Mouse model of

CVB Myocarditis

Marholdt, H, etal. Circulation 2004

Epicardial-Mid Wall

Myocarditis: MRI and Histology

Fairweather, DL, Cooper, LT, et al

European Heart Journal, Volume 40, Issue Supplement_1, October 2019, ehz748.0565,

https://doi.org/10.1093/eurheartj/ehz748.0565

Detection Rate of Myocarditis

by MRI

2009 versus 2018 Lake Louise Criteria for Diagnosis of Acute Myocarditis

Leutkens, JA et al Radiology: Cardiothoracic Imaging 2019: 1(3)

Time Course of Native T1 and T2 Recovery in Acute

Myocarditis

Hinojar R et al. JACC Cardiovasc Imaging. 2015

Hinojar R J Cardiovasc Magn Reson. BioMed Central; 2014

Histologic “Dallas” Criteria

Aertz, et al Am J Pathol 1986

Sampling error, Variation in interpretation,

Low sensitivity, Lack of correlation with outcome

Baughman, K, Circulation 2006

Immuostains for the Diagnosis of Myocarditis

Nakayama et al EJHF 2017

CD3 CD68 CD163

Number of Inflammatory Cells Predicts Outcome in Myocarditis

Nakayama et al EJHF 2017

CD3-T cells CD68- Macrophages

Innsbruck and Maastricht

Inflammatory Cardiomyopathy Registry

Circ Heart Fail. 2018 ≥14 infiltrating inflammatory cells/mm2

AZA + Pred

↑ survival

• 374 patients with suspected myocarditis

• Chest pain 95%

• Age 35, 73% male; LVEF 62%

• Median FU 4.3 years

• Events: 26/374.

ITAMY Study Ten Center Italian Registry

2006-2013

Aquaro, et al JACC 2017

Anteroseptal Pattern on MRI Increased risk of MACE

Aquaro, et al JACC 2017

5 yr event probability 0.36 in AS group

• 670 patients with suspected myocarditis

• Chest pain 52% (LV dysfunction/ dyspnea 30%; Rhythm problems 18%)

• Age 47, 59% male; 13% QRS>120 ms

• All had MRI -294 with DGE

• Median FU 4.7 years

Brigham and Women’s Hospital MRI Case Series

2002-2015

Grani, C et al JACC 2017

DGE on CMR associated with greater risk of MACE

Grani, C et al JACC 2017

Annualized Risk of Death varies with LVEF and DGE

Grani, C et al JACC 2017

Ventricular Arrhythmias and Sudden Cardiac Death in Lymphocytic

Myocarditis

• Risk 0 after resolution of DGE

• Risk increased if DGE increases

Peretto. Et al, 25 (9) March 10th 2020

Cooper, LT JACC 25 (9) March 10th 2020

Kociol, R, Cooper, LT et al

Circulation February 2020

58 yo Woman admitted October 23, 2019

ECG Low QRS voltage due to myocardial edema An injury current with ST elevations in contiguous leads Pericarditis with PR segment changes may also be present Troponin is almost always elevated in 1st week* Echo May show normal LVEDD and left ventricular hypertrophy

Fulminant Myocarditis Sudden and severe inflammation resulting in myocyte necrosis,

edema, and cardiogenic shock.

Courtesy of Bill Edwards

Algorithm for the Evaluation of Suspected Myocarditis

in the Setting of Unexplained Acute DCM

Bozkurt, et al. Circulation, 2016

Unexplained Acute

Cardiomyopathy*

Required inotropic or mechanical circulatory support,

Mobitz type 2 second degree or higher heart block, sustained

or symptomatic ventricular tachycardia or failure to respond to

guideline based medical management within 1-2 weeks?

Yes-Endomyocardial Biopsy

COR I/LOE B

No-Cardiac MRI

COR 2B/LOE C

*Usually a dilated cardiomyopathy. Fulminant myocarditis may have normal end diastolic diameter with mildly thickened walls. Excluded ischemic, hemodynamic (valvular, hypertensive), metabolic, and toxic causes of cardiomyopathy as indicated clinically.

Survival in Fulminant Versus Nonfulminant Acute Myocarditis n=187

Enrico Ammirati, Circulation August 2017

Mason et al, NEJM. Aug 9th, 1995

No effect of Prednisone + AZA or CSA in LVEF or Survival

JACC, October 2017

Prognosis in Myocarditis Varies by Histology

0.0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5

Cooper, et al: N Engl J Med 1997 336:1860-66

Years

Pro

po

rtio

n s

urv

ivin

g

Giant-cell myocarditis

Lymphocytic myocarditis

P<0.0001

When to Suspect Giant Cell Myocarditis

• Rapidly Progressive course

• Failure to Respond to Usual Care

• Ventricular Tachycardia

• High-grade Heart Block

8 Of 28 (29%) screened subjects

in the GCM Trial had GCM

Cooper, LT. et al. Am Ht J 2008

Endomyocardial biopsy before and after OKT3, CSA, Steroid

immunosuppression

Sensitivity of EMB for GCM is 80-85%

Kandolin, R et al Circ HF 2013

GCM survival treated with Multidrug Immunosuppression

Eosinophilic Myocarditis

Brambatti, et al. JACC Nov 7th 2017

Clozapine: Example of Drug Hypersensitivity

• Myocarditis: Up to 1:1000

• 50/213 cases fatal

• 85% occur in first 2 months

of treatment

• Eosinophilia up to 66%

De Berardis, DD et al. Current Drug Safety 2012

Ben m’rad M, et al. Medicine 2009

• Prevalence of Myocarditis 1.14%

• CHB 3; CV shock 3; CV arrest 4 cases

• Overall 46% MACE rate over 102 days

• Median time from treatment 34 days

• Higher dose steroids associated with lower troponin and MACE rates

Checkpoint Inhibitor Myocarditis 8 Centers; n=35

Mahmood, SS JACC 2018

• Cardiotoxicity presents within 2 months with CHF or ventricular arrhythmias. MRI or biopsy

• Start methylprednisolone 1-2 mg/kg

• If deterioration, consider adding abatacept Annals of Oncology 2017

Brahmer, JR et al. J Clin Onc 2018

Insert image of page- Brahmer JR, et al. Management of

immune-related adverse events in patients treated

with immune checkpoint inhibitor therapy: American

Society of Clinical Oncology

clinical practice guideline. J Clin Oncol 2018;36:1714-

1768.

©2012 MFMER

| slide-37

48 year old woman with Complete Heart Block

Birnie, D et al 2014

Algorithm for the

Evaluation of Cardiac

Sarcoidosis

Sites of Cardiac Sarcoidosis at Autopsy

Kandolin 2015

Differential Diagnosis:

ARVC/ALVC

Myocarditis

Other Systemic Causes of

cardiac Inflammation:

eg.GPA

©2012 MFMER

| slide-40

SA

HLA

VLA

13N-NH3 defects and matched 18F-FDG uptake

associated with Cardiac Sarcoidosis

NH3 FDG

Cardiac PET and Prognosis in known or suspected CS

Blankstein, JACC 2014

Chareonthaitawee, P, J Nucl Cardiol. 2017

• Abnormal myocardial perfusion and metabolism had a four-fold increase in the annual rate of ventricular tachycardia or death compared to patients with normal imaging (n= 118)

• SNMMI Position Statement on The Role of PET/CT in Cardiac Sarcoidosis- August 2017

Baseline Following Infliximab

Courtesy of Jukka Lehtonen

FDG PET can follow

Response to Treatment

2020 Summary of Management of Acute/Fulminant Myocarditis

• All- GDMC and hemodynamic support- unloading if possible; avoid sports for 3-6 months.

• GCM- Immunosuppression including cyclosporine or tacrolimus; ATG or Campath, ICD if expected survival > 1 year.

• Checkpoint Inhibitor- Corticosteroids, Abatacept?

• Eosinophilic- Corticosteroids, Mepolizumab?

Cooper.leslie@mayo.edu

Randomized Clinical Trials 2020-2022

• IVIG for PVB19 positive Chronic DCM NCT 000659386- Maastrict

• Secukinumab (anti IL-17) for Acute myocarditis -Frankfurt

• Anakinra 100 mg SQ for CPI Myocarditis- until hospital discharge or a maximum of 14 days -Paris

• CASTT- Canadian Sarcoidosis Tx Trial (CHASM-CS; CHIR IRSC- Ottawa Heart)

• eMAP -electrogram biopsy(U Penn; Mayo)

Cardiac MRI and Biopsy with Sarcoidosis