pavlisko cv evening specialty uscap 2016handouts.uscap.org/2016_card_pavli_1.pdfa tale of two...

4/12/2016

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ACCME/DisclosuresThe USCAP requires that anyone in a position to influence or control the content of CME disclose

any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their

spouse/partner have, or have had, within the past 12 months, which relates to the content of

this educational activity and creates a conflict of interest.

Dr. Pavlisko declares she has no conflict(s)

of interest to disclose.

A Tale of Two Hearts: Case 1

Elizabeth N. Pavlisko, MDAssistant Professor of PathologyDuke University Medical Center

Durham, NC USA

A Tale of Two Hearts: Case 1

• Case presentation & diagnosis

• What can we learn from apical core samples following ventricular assist device placement

• Special techniques

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Case 1: Clinical History

• 60 year old female

• History of nonischemic cardiomyopathy, rheumatoid arthritis, peptic ulcer disease and hypertension.

• She was admitted in October for acute decompensated heart failure with AV nodal reentry tachycardia.


• Her hospital course was complicated, and she was admitted to the CCU in cardiogenic shock.

• A balloon pump was placed, and 2 inotropes were simultaneously initiated.

• She had episodes of atrial fibrillation and atrial flutter and was loaded with amiodarone with subsequent conversion to a normal sinus rhythm.


• In December she was readmitted for low output heart failure

• A right heart catheterization was performed• right atrial pressure: mean 14 • right ventricular pressure: 32/15• pulmonary artery pressure: 32/15, mean 21• pulmonary capillary wedge pressure: mean 16 • cardiac index 1.7

• She was initiated on inotrope support with a milrinone infusion

• Subsequently, a left ventricular assist device (LVAD) was placed.

• The apical core from LVAD implantation was submitted to Pathology for evaluation


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Congo Red Trichrome

Thick Section

- Myofibril loss

- Accumulation of lamellar bodies

- Lipofuscin

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Electron micrographs, low magnification

Electron micrograph, higher magnification

Thin Section-Myeloid bodies(lamellar bodies)

-Curvilinear bodies-Mega mitochondria

What is your diagnosis? Differential Diagnosis for Vacuolar Myopathy

• Storage disorders• Alpha galactosidase (Fabry disease)• Type II glycogen storage disorder (Pompe)• Type III glycogen storage disorder (Cori disease)• Type V glycogen storage disorder (Andersen disease)• Danon disease• PRKAG2 mutations

• Mitochondrial myopathy• Primary carnitine deficiency

• Ischemic heart disease

• Chloroquine toxicity

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Differential Diagnosis for Vacuolar Myopathy

• Storage disorders• Alpha galactosidase (Fabry disease)• Type II glycogen storage disorder (Pompe)• Type III glycogen storage disorder (Cori disease)• Type V glycogen storage disorder (Andersen disease)• Danon disease• PRKAG2 mutations

• Mitochondrial myopathy• Primary carnitine deficiency

• Ischemic heart disease

• Chloroquine toxicity

Chloroquine Toxicity


• Chloroquine (1930’s) and hydroxychloroquine (1950’s)

• First used for malaria prophylaxis/treatment and later indicated for autoimmune disorders.

• Administered orally, identical pharmacokinetics and high bioavailability


• Chloroquine interferes with normal lysosomal pH maintenance

• pH alteration enzyme dysfunction

• Net effect:• disrupted lysosomal vesicle formation • accumulation of glycogen and phospholipids

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• Accumulation occurs in melanin containing cells, skeletal muscle, cardiac muscle and in parenchymal organs

• Side effect profile of chloroquine is well described

−gastrointestinal−hematologic toxicity− retinopathy−myopathy (skeletal muscle)/ neuropathy−cardiac toxicity


• Diagnostic considerations in the setting of suspected cardiac toxicity:

−heart disease attributable to the underlying autoimmune disease

−additional medications the patient may be taking ( e.g. anthracyclines, colchicine etc.)

−ischemic cardiomyopathy

Chloroquine ToxicityRisk factors for CHC cardiomyopathy?No clear established duration or dosePossible polymorphism in cytochrome P450 2C8

Reversal of symptoms with discontinued therapy?Sometimes

Tonnesmann (2013): reviewed 40 patients with CHC toxicity• Age: 31-81 years• Cumulative dose: 15-5040 grams• Duration of treatment: 2-35 years• Cardiomyopathy occurred in those with longer treatment and

greater cumulative dose (average = 14 years/1640 grams)Tonnesman et al. Immunopharmacol and Immunotoxacol 2013;35:434-442.


• She was initiated on inotrope support with a milrinone infusion. Subsequently, a left ventricular assist device was placed.

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Apical Core Pathology Apical Core Pathology

What can we learn from an apical core?

• Apical core may be the first opportunity to refine a clinical diagnosis of idiopathic cardiomyopathy

• What we can glean from a apical core is similar to that of an endomyocardial biopsy with benefit of increased sample size

Apical Core Pathology

What can we learn from an apical core?

• Clinical history, function and morphology are important


Idiopathic/Genetic Secondary

Cardiomyopathy

NCARVCHCMRCMDCM

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Dilated Cardiomyopathy

−Idiopathic/genetic−Ischemia−Hypertension−Infectious

−Autoimmune−Toxic −Peripartum−Uremia−Endocrine dysfunction


Restrictive Cardiomyopathy

−Idiopathic/genetic−Infiltrative (amyloid, sarcoid, hemosiderosis)−Storage disorder−Endomyocardial disorders

− Endomyocardial fibroelastosis− Drug toxicity− Hypereosinophilic syndrome


Hypertrophic Cardiomyopathy

-most common genetically determined cardiac disease • 1 in 500

-mutations in sarcomere and sarcomere-like proteins• beta myosin heavy chain (MYH7)• myosin-binding protein C (MBPC)

-autosomal dominant trait with incomplete penetrance

-myofiber disarray

**hypertension, aortic stenosis, storage/infiltrative** disorders must be excluded


• Strecker (2004)−223 apical cores from VAD placement −Most common clinical diagnosis = DMC or ICM−Concluded findings are non-specific

Strecker et al. Int J Clin Exp Pathol 2004;7:5549-5556.

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Apical Core PathologyUnexpected findings

• Systemic sarcoidosis− 5% with clinical evidence of cardiac involvement− 25% have cardiac involvement at autopsy

• Systemic sarcoidosis−Segura (2014)

6/177 patients (2003-2013) with granulomatous myocarditis on apical core

−Syugo (2013)1 patient diagnosed on apical core

−Roberts (2009)3 patients diagnosed on apical core

• GC myocarditis−Anderson (2013):

1 patient suspected adriamycin toxicity with apical core showinglymphocytic myocarditis -> EMB showed GC myocarditis



• Malignancy−Philipsen (2013): 44 yo female with ST elevated MI.

Apical core demonstrated acute infarct and tumor cells caught in thrombus (fibrolamellar HCC)

• Amyloid

• Toxicity related to therapy

• Storage disorder


Are apical core findings predictive/prognostic?Grading the extent/severity of fibrosis and/or myocyte hypertrophy

• Segura, Cardiov Pathol 2011(ability to wean)

• Soderlund, Cardiov Pathol 2009 (mortality at 1 yr and PCWP improvement)

• Matsumiya, JHLT 2005 (ability to wean)

• Bruckner, JHLT 2004 (EF improvement)

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Apical Core Pathology• Apical cores provide an opportunity to refine a

diagnosis of idiopathic cardiomyopathy

• Unexpected findings are possible

• Extent of fibrosis and myocyte hypertrophy may provide useful information

Special Techniques

Special Techniques

• Formalin-fixed, paraffin-embedded

• Frozen

• Fixation for ultrastructural analysis

Special Techniques for Evaluation of Apical Cores and EMBs

Formalin‐fixed, paraffin‐embedded tissueCollagen Masson/Mallory trichrome

Histochem

ical Stains Elastin Movat pentachrome

Verhoeff‐Van Gieson (VVG)

Glycogen PAS +/‐ diastaseIron Prussian Blue

Perl's iron

Amyloid* Congo red

Sulfated alcian blue

Immuno Stains Inflammatory infiltrate CD45, CD20, CD3, etc.

Amyloid* Transthyretin

Kappa and lambda

ApolipoproteinAmyloid A

Tumor typing Panel based on morphology

Fresh frozen tissueAmyloid* Immunofluorescence

Protein sequencing

Viral myocarditis Viral PCR

Glutaraldehyde or Karnowsky fixed tissue

Storage diseasesStructural disorders

Mitochondrial disease

Drug toxicity

*Mass spectrometry for amyloid protein identification can be performed on FFPE

Special Techniques

Formalin-fixed, paraffin-embedded tissueHistochemical Stains• Hematoxylin and Eosin• Trichrome• Congo red• Periodic acid-Schiff with diastase• VVG elastin

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H&E TrichromeMyofibrillar myopathy

Amyloid - nodular

- perivascular

- interstitialCongophilic material on

congo red stain

Dichroic birefringence under polarized light

Amyloid

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Special Techniques

Formalin-fixed, paraffin-embedded tissueImmunohistochemical Stains• LCA/CD45• Lymphocytes CD3 and CD20• Macrophages/histiocytes CD68• Kappa and lambda• Selected panel for tumor typing

Special Techniques

• Formalin-fixed, paraffin-embedded• Frozen tissue• Fixation for ultrastructural analysis

Special Techniques

Frozen tissue• Immunohistochemical stains

• Immunofluorescence

• Protein sequencing

• Viral PCR

Special Techniques

• Formalin-fixed, paraffin-embedded• Frozen• Fixation for ultrastructural analysis

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Special Techniques

Glutaraldehyde or Karnowsky fixed tissueUltrastructrual evaluation• Amyloid versus light chain disease• Storage disorders• Structural abnormalities• Mitochondrial disease• Drug toxicity

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