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C A R D I O L O G Y G R A N D R O U N D S
Title:
Cardiology Case Carousel
Speaker: Benjamin K. Johnson, MD Cardiovascular Disease Fellow Minneapolis Heart Institute® at Abbott Northwestern Hospital & Hennepin County Medical Center
Date: Monday, January 11, 2016
Time: 7:00 – 8:00 AM
Location: ANW Education Building, Watson Room OBJECTIVES At the completion of this activity, the participants should be able to:
1. Identify the genetic mutations in ARVC. 2. Describe the pathophysiology of ARVC. 3. Understand the imaging characteristics in patients with ARVC.
Physician: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Allina Health and Minneapolis Heart Institute Foundation. Allina Health is accredited by the ACCME to provide continuing medical education for physicians.
Allina Health designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurse: This activity has been designed to meet the Minnesota Board of Nursing continuing education requirements for 1.2 hours of credit. However, the nurse is responsible for determining whether this activity meets the requirements for acceptable continuing education.
DISCLOSURE STATEMENTS Speaker Dr. Benjamin has declared that he does not have any conflicts of interest to disclose.
Planning Committee Dr. Michael Miedema, Dr. Scott Sharkey and Jolene Bell Makowesky have declared that they do not have any conflicts of interest associated with the planning of this activity. Dr. Robert Schwartz declared the following relationship - consultant: Boston Scientific.
PLEASE SAVE A COPY OF THIS FLIER AS YOUR CERTIFICATE OF ATTENDANCE
Signature: __________________________________________________________________________ My signature verifies that I have attended the above stated number of hours of the CME activity.
Allina Health - Learning & Development - 2925 Chicago Ave - MR 10701 - Minneapolis MN 55407
1
Cardiology Case Carousel Genetic Cardiomyopathy
Benjamin K. Johnson, MD
January 11, 2016
Revised Learning Objectives
• Identify the genetic mutations in ARVC
• Describe the pathophysiology of ARVC
• Understand the imaging characteristics in patients with ARVC
2
Case 1
20 y.o. ♀ with Chest Pain in the ED
• HPI (September 2014): Developed acute onset substernal chest pain while studying in
the library
Pain progressively worsened
Presented to Missouri Baptist in St. Louis for further evaluation
• Social Hx: Studying biomedical engineering at Washington University in
St. Louis
Regular “intense” kickboxing routine
No illicit drug, EtOH or tobacco abuse
3
• Family History: Mother – Diagnosed with cardiomyopathy at age 20
♦ Etiology thought to be viral myocarditis
♦ S/p heart transplant age 22 (28 years prior) at Stanford University (Details unknown – Original records destroyed)
♦ Died 2012
• VS: BP 129/82, HR 90
• Exam: Unremarkable
• Lab: WBC 20, Troponin I 110, CK-MB 284
• EKG:
20 y.o. ♀ with Chest Pain in the ED
Invasive Coronary Angiography(Images not available)
1. Normal coronary arteries
2. Mildly elevated filling pressures
3. LV gram: EF 35% on LV gram with regional WMA anterolateral, inferolateral
Transthoracic Echo(images not available)
1. LVEF 30-35%
2. Anterolateral WMA
20 y.o. ♀ with Chest Pain in the ED
4
Troponin I, trend: 110 178 276 ng/ml
Impression:“Lateral MI in a 20 yo woman with no risk factors for CAD. This was almost certainly coronary spasm. Her history is not suggestive of viral cardiomyopathy.”
Plan:- ASA, Norvasc & Coreg
- Discharge home
20 y.o. ♀ with Chest Pain in the ED
• Cardiology follow up in St. Louis (December 2014) “She had been seeing a therapist prior to her MI and the
therapist is now questioning whether she should be on a sedative for stress”.
Repeat TTE: LVEF improved to 45%, anterolateral WMA persists
• Presented to MHI for a second opinion (May 2015) Asymptomatic and doing well
Given family history of cardiomyopathy in mother, cMRIordered
20 y.o. ♀ with Presumed Coronary Vasospasm
5
20 y.o. ♀ with Presumed Coronary Vasospasm
• Presented to ANW ED with acute onset chest pain (June 2015) HPI: Epigastric/chest pain while driving. Similar but less
severe to pain with prior STEMI. Symptoms reproducible with standing.
VS: BP 115/63, HR 73
Exam: Unremarkable
EKG:
Lab: Troponin I trend 0.058 0.078 0.065 0.069
20 y.o. ♀ with Presumed Coronary Vasospasm
Assessment:1. Mildly reduced LVEF, 48%2. RV function mildly reduced
Plan:- cMRI
6
20 y.o. ♀ with Presumed Coronary Vasospasm
cMRI Sequence for DE1. Mild increase in LVEDd, LVEF
46%2. RV is normal3. Marked DE in the inferolateral,
lateral and anterolateral walls, primarily subepicardial
4. Consistent with myocarditis
20 y.o. ♀ with Presumed Coronary Vasospasm
• Right Heart Catheterization with Biopsy
RA: 5 mmHg | RV 21/7 | PA 26/3 (12) | PCWP 8 mmHg
Thermodilution CO/CI: 5.7/3.7 | Fick CO/CI: 5.3/3.4
• 5 Biopsy Samples:
Normal myocardium
No inflammation or infiltrative process
7
20 y.o. ♀ with Presumed Coronary Vasospasm
• Symptoms resolved
• Lab: HIV negative, TSH, ferritin and ACE level all normal
• Continuous Telemetry: Scattered PVC’s, no arrhythmias
• Assessment:
Familial cardiomyopathy vs myocarditis vs infiltrative cardiomyopathy
• Plan:
Start Lisinopril, continue Coreg
Discharge home with close follow up in heart failure clinic
Genetic cardiomyopathy panel as outpatient
20 y.o. ♀ with Presumed Coronary Vasospasm
• Outpatient Advanced Heart Failure Clinic Visit Some palpitations
NYHA II symptoms
Lab: Troponin 1.9
Assessment:♦ Still no unifying diagnosis
♦ Concerning family history, uptake on cMRI, persistently elevated troponin and low voltage on EKG
♦ May need to consider EP guided LV biopsy
Plan:♦ Continue ARB & BB, add spironolactone
♦ Genetic cardiomyopathy panel sent
♦ Referral to Genetic Arrhythmia Clinic
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• Genetic cardiomyopathy panel Panel tests for 76 gene mutations associated with cardiomyopathy
(ARVC, HCM, LVNC, DCM & Noonan syndrome)
10 week turn-around time
• Results:
• Interpretation:
DSP mutation is associated with ARVC & Carvajal syndrome
MYBPC3 is non-specific (Reported in up to 40% of patients with familial HCM, 2-3% of familial DCM & infrequently in LVNC. Also found in normal patients)
Coding DNA Variant Zygosity Classification
DSP c.1691 C>T p.Thr564Ile (T564I) HeterozygousVariant, likely disease
causing
MYBPC3
c.2497 G>A p.ALA833Thr (A833T) HeterozygousVariant of unknown
significance
20 y.o. ♀ with Presumed Coronary Vasospasm
1 2 3 4 5
6 7 8 9 10 11 12
13 14 15 16 17 18
19 20 21 22 Sex
Desmoplakin
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Case 2(Brother of Case 1)
• Initial Contact (June 2015): Patients father calls MHI requesting a TTE for the patient given
family history of cardiomyopathy
Patient is reportedly asymptomatic
• Social Hx: Studying mechanical engineering at Washington University in
St. Louis.
Avid weightlifter (bench press 250 lbs) & runner (7 minute mile pace)
No illicit drug, EtOH or tobacco abuse
• TTE ordered
19 y.o. ♂ with Family History of Cardiomyopathy
10
Assessment:Dilated LV with low normal LVEF, 58%Plan:- cMRI
cMRI Functional Sequence:
1) Mildly increased LV volume2) LVEF 43%3) Mildly increased RV volume with global hypokinesis4) RVEF 39%
11
cMRI Sequence for DE1) Extensive subepicardial DE of lateral & inferolateral walls (non-ischemic pattern) 2) DE of inferior and lateral RV walls
19 y.o. ♂ with Family History of Cardiomyopathy
• Initial Cardiology Visit (August 2015): Remains asymptomatic
VS: BP 126/84, HR 68, BMI 22
Exam: Displaced PMI, otherwise unremarkable
Results of TTE and cMRI discussed with the patient
Plan:
♦ Start Coreg
♦ Limit extreme exercise
♦ Referral to advanced heart failure service
12
19 y.o. ♂ with Family History of Cardiomyopathy
• Advanced Heart Failure/Genetic Arrhythmia Clinic Visit (August 2015): Remains asymptomatic
VS: BP 104/60, HR 71
Exam: Unremarkable
Baseline EKG
Plan:
♦ Start Lisinopril & continue Coreg
♦ Send focused genetic testing for DSP mutation
19 y.o. ♂ with Family History of Cardiomyopathy
• Results:
• Plan: Primary prevention ICD implantation planned
Result Coding DNA Variant Zygosity Classification
DSP PRESENT c.1691 C>Tp.Thr564Ile
(T564I)Heterozygous
Variant, likely disease causing
MYBPC3 Not Tested N/A N/A N/A N/A
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• December 2015 - Presented to ANW ED with acute onset chest pain.
• VS: BP 130/71, HR 58
• Exam: Unremarkable
• Lab: WBC 18, TroponinI 29.3, ESR 3
• EKG:
• Cath lab activated
19 y.o. ♂ with Family History of Cardiomyopathy
Coronary angiography:Normal coronary arteries
19 y.o. ♂ with Family History of Cardiomyopathy
14
Transthoracic Echo:1. LVEF 40-45%2. Anterolateral WMA
19 y.o. ♂ with Family History of Cardiomyopathy
Troponin I trend: 29 161 184 ng/ml
Impression:Concern for progression of familial cardiomyopathy with possible overlying myocarditis
Plan: Obtain cMRI
19 y.o. ♂ with Family History of Cardiomyopathy
15
cMRI Functional Sequence:
1) Mild-moderate increase in LV volume2) LVEF 39%3) New anterior apical and apical septal WMA3) Mildly increased RV volume with global hypokinesis4) RVEF 42%
cMRI Sequence for DE1) Marked progression of
myocardial inflammation to essentially all segments
2) Endocardium spared except true apex where DE is transmural
16
19 y.o. ♂ with Family History of Cardiomyopathy
• CT Chest, Abdomen & Pelvis No mediastinal lymphadenopathy or skeletal lesions making sarcoid
and myeloma/amyloid respectively less likely
• Assessment: Diagnosis unclear but likely Carvajal syndrome with biventricular
ARVC
• Plan: Discharged on HD#3
Start Apixaban (LV apical thrombus prophylaxis)
Life vest
Repeat cMRI in 3 months
Primary prevention ICD after repeat cMRI
Coreg & lisinopril continued, spironolactone started
Case 1 Case 2
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Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
• Described in the 1980’s
• Genetic cardiomyopathy (genes encoding 5 desmosomal proteins) Desmoplakin (DSP), plakoglobin, plakophilin, desmoglein &
desmocollin
• Clinical phenotype – Arrhythmia, SCD & heart failure
• Pathologic phenotype – Fibrofatty replacement of the RV myocardium.
• Prevalence: Probably 1:1000 - 1:2000
• Major cause of SCD in the young & athletes
• Complex diagnostic criteriaOrphanet J Rare Dis. 2007 Nov 14; 2:45
Proposed Pathophysiology of ARVC
Impaired desmosome function
Mechanical stress Myocytedetachment
Cell death/apoptosis
Inflammation & edema as tissue attempts to repair itself
Fibrofatty replacement
18
Genetics of ARVC
• 2 Forms of ARVC
Autosomal dominant form (ARVC 1-9)
♦ ARVC8 – Desmoplakin mutation
♦ Develop arrhythmias and heart failure in adolescence
Autosomal recessive form – Cardiocutaneous syndrome
♦ Nexos Syndrome – Homozygous plakoglobin mutation
♦ Carvajal Syndrome – Homozygous desmoplakin mutation
Carvajal Syndrome
• Initially described by an Equadorian dermatologist - Luis Carvajal-Huerta, MD.
• Later discovered in an Iranian family
• Clinical phenotype - ARVC with Palmoplantar keratoderma & woolly hair.
• Biventricular involvement common.
Clin Res Cardiol (2011) 100:1087–1093
19
Several Questions Remain…
1. Can someone with a heterozygous mutation develop autosomal recessive disease?
2. Why did the cMRI have the appearance of myocarditis?
3. Why did both patients present with acute STEMI?
4. Why was there regionality to the inflammation?
“We identified a single heterozygous de novo mutation in the desmoplakingene DSP, p.Thr564Ile, leading to severe combined cardiac/dermatological phenotypes”
Can someone with a heterozygous mutation develop autosomal recessive disease?
20
How can someone with a heterozygous mutation develop autosomal recessive disease?
• Haploinsufficiency: Diploid organism with a single functional copy of a gene & the
other copy inactivated by mutation
Single functional copy does not produce enough protein leading to disease state
Why did the cMRI have the appearance of myocarditis?
Impaired desmosome function
Mechanical stress Myocytedetachment
Cell death/apoptosis
Inflammation & edema as tissue attempts to repair itself (Acute)
Fibrofatty replacement (Chronic)
T1-Weighted SequenceBright = Fat
• Pathologic study of 30 autopsy hearts with ARVC.• Scattered foci of lymphocytes in the areas of cell death observed in 70%• Suggests inflammatory process (myocarditis) is involved in the pathogenesis
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“It has been suggested that patients with ARVC/D may be predisposed or
susceptible to viral myocarditis, which could lead to a decrease in cardiac
function and accelerate progression of the disease.”
“The link between ARVC/D and myocarditis is still undefined.”
Circulation. 2010;121:1533-1541.
Why did the cMRI have the appearance of myocarditis?
Why did both patients present with acute STEMI?
• 11 patients with AMI later diagnosed with myocarditis
7 met criteria for STEMI on initial EKG
Initial CK in these 7 patients ranged from 30 to 1518
LVEF was normal in 5 of 7 patients
22
Why was there regionality to the inflammation?
J Am Coll Cardiol Img. 2015;8(5):597-611.
Thank You!