bkj mhi grand rounds 1.11.15 · invasive coronary angiography (images not available) 1. normal...

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

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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

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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

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• 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:


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


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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


• 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

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• 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


Assessment:1. Mildly reduced LVEF, 48%2. RV function mildly reduced

Plan:- cMRI

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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


• 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

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• 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


• 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


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

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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%

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cMRI Sequence for DE1) Extensive subepicardial DE of lateral & inferolateral walls (non-ischemic pattern) 2) DE of inferior and lateral RV walls


• 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

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• 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


• 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


Coronary angiography:Normal coronary arteries


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Transthoracic Echo:1. LVEF 40-45%2. Anterolateral WMA


Troponin I trend: 29 161 184 ng/ml

Impression:Concern for progression of familial cardiomyopathy with possible overlying myocarditis

Plan: Obtain cMRI


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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

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• 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

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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

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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?

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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

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Why was there regionality to the inflammation?

J Am Coll Cardiol Img. 2015;8(5):597-611.

Thank You!

bkj mhi grand rounds 1.11.15 · invasive coronary angiography (images not available) 1. normal...

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