4/12/2016
1
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
4/12/2016
2
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.
Case 1: Clinical History
• 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.
Case 1: Clinical History
• 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
Case 1: Clinical History
4/12/2016
3
Congo Red Trichrome
Thick Section
- Myofibril loss
- Accumulation of lamellar bodies
- Lipofuscin
4/12/2016
4
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
4/12/2016
5
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 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 Toxicity
• Chloroquine interferes with normal lysosomal pH maintenance
• pH alteration enzyme dysfunction
• Net effect:• disrupted lysosomal vesicle formation • accumulation of glycogen and phospholipids
4/12/2016
6
Chloroquine Toxicity
• 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
Chloroquine 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.
Case 1: Clinical History
• She was initiated on inotrope support with a milrinone infusion. Subsequently, a left ventricular assist device was placed.
4/12/2016
7
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
Apical Core Pathology
Idiopathic/Genetic Secondary
Cardiomyopathy
NCARVCHCMRCMDCM
4/12/2016
8
Apical Core Pathology
Dilated Cardiomyopathy
−Idiopathic/genetic−Ischemia−Hypertension−Infectious
−Autoimmune−Toxic −Peripartum−Uremia−Endocrine dysfunction
Apical Core Pathology
Restrictive Cardiomyopathy
−Idiopathic/genetic−Infiltrative (amyloid, sarcoid, hemosiderosis)−Storage disorder−Endomyocardial disorders
− Endomyocardial fibroelastosis− Drug toxicity− Hypereosinophilic syndrome
Apical Core Pathology
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
Apical Core Pathology
• 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.
4/12/2016
9
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
Apical Core PathologyUnexpected findings
Apical Core PathologyUnexpected findings
• 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
Apical Core Pathology
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)
4/12/2016
10
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
4/12/2016
11
H&E TrichromeMyofibrillar myopathy
Amyloid - nodular
- perivascular
- interstitialCongophilic material on
congo red stain
Dichroic birefringence under polarized light
Amyloid
4/12/2016
12
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
4/12/2016
13
Special Techniques
Glutaraldehyde or Karnowsky fixed tissueUltrastructrual evaluation• Amyloid versus light chain disease• Storage disorders• Structural abnormalities• Mitochondrial disease• Drug toxicity