Clinical Pathologic Conference
Division of Cardiology
Andrew Bolin
May 11th, 2007
The Case
 Chief Complaint: Irregular Heart Beat, Dyspnea
and Fatigue.
 HPI: A 74 year old white female with a history
of paroxysmal atrial fibrillation for 7 years is
referred to the cardiology clinic.
 The patient had intermittent paroxysms of
atrial fibrillation while taking flecainide for 5
years. In the month prior to referral, she was
hospitalized twice for rapid atrial fibrillation.
The Case
 Before the first hospitalization, the patient
reported symptoms of: paroxysmal nocturnal
dyspnea, orthopnea and dyspnea on exertion.
 During the first hospitalization, flecainide was
discontinued and warfarin and metoprolol were
started. She ruled out for an acute myocardial
infarction and a dipyridamole thallium study
did not demonstrate ischemia. An echocardiogram revealed normal left ventricular
function and a mildly enlarged left atrium.
The Case
 Two weeks prior to her second hospitalization,
the patient experienced the sudden onset of:
fatigue, decreased endurance, irregular heart
beat, constant chest pressure and profound
dyspnea on exertion.
 Prior to this illness, the patient could ambulate
for thirty minutes without fatigue or dyspnea.
On the day of consultation she experienced
dyspnea on walking 20 yards.
 Review of Symptoms: Positive for: 10 pound
weight gain, diffuse chronic myalgias, and
anxiety
Past Medical History
 Hypertension for 11 years
 Breast Cancer: underwent left
mastectomy and chemotherapy 14 years
before. No radiation therapy.
 Recurrent Urinary Tract Infections
Social History
 Married to retired
Methodist minister
 Two adult children
 No alcohol, tobacco
or illicit drugs
 No unusual
exposures
Family History
 Mother died of
congestive heart
failure at age 79
 Sister breast cancer
 Sister “bone cancer”
Medications
 Metoprolol 25 mg BID  Allergies:
Macrodantin
 Coumadin
 Hydrochlorothiazide
25 mg Daily
 Celexa 10 mg Daily
 Aspirin 81 mg Daily
 Bactrim DS three
days per week
Physical Exam
 Blood Pressure 148/78 (in both arms)
Pulse 90 Respirations 18
 Neck: normal jugular venous pressure,
symmetric brisk carotid upstrokes
without bruits, no lymphadenopathy
 Lungs: clear to auscultation, dullness to
percussion in right base
Physical Exam
 Cardiac: normal point of maximal impulse,
normal S1, physiologically split S2, no
murmurs, rubs or gallops, strong and
symmetric peripheral pulses
 Benign Abdominal Exam
 Extremities: no clubbing, cyanosis or edema
 Musculoskeletal: tenderness to palpation in
trapezius and shoulder girdle bilaterally
Studies
 Electrocardiogram: atrial fibrillation,
incomplete right bundle branch block
and nonspecific ST-T abnormalities
 Chest X-ray: possible right pleural
effusion
 Transesophageal Echocardiogram:
unusual thickening of left atrial walls,
small pericardial effusion
Studies
 Chest CT: pericardial effusion and
bilateral pleural effusions, biapical
pleuroparenchymal scarring
 Cardiac MRI: atrium unremarkable
 Labs: CBC, E-group, BUN, Creatinine,
TSH, Troponin and CK were all within
normal limits.
Right Thoracentesis
 Consistent with Transudative Effusion
 WBC 485, Lymphocytes 89%
 Flow Cytometry: Consistent with a
Reactive Effusion.
 Cytology: No Malignant Cells
Case Summary
 Elderly White Female with A-fib
 Progressive Symptoms of CHF Over Weeks
Without Echocardiographic Evidence of LV
Dysfunction
 Transudative Lymphocytic Bilateral Pleural
Effusions
 Biapical Pleuroparenchymal Scarring
 Pericardial Effusion Without Evidence of
Tamponade
 Incomplete Right Bundle Branch Block
 Abnormal Left Atrial Walls
Case Summary
 The Patient Has a Pathologic Process
Involving the Pericardium and
Myocardium that is Not Related to
Valvular or Ischemic Disease.
Additionally, Noted is an
Echocardiogram Demonstrating Highly
Abnormal Left Atrial Walls.
Causes of Lymphocytic Pleural
Effusions









CHF (Only Transudate)
Neoplasm
Fungal Infection
TB
Sarcoidosis
Rheumatoid Arthritis
Hepatic Hydrothorax
Yellow Nail Syndrome
Chylothorax
Causes of Left Atrial
Enlargement







Valvular Disease
Myocardial Infarction
Obstructive Cardiomyopathy
Hypertension
Infiltrative Cardiomyopathy
Inflammatory Cardiomyopathy
Primary or Metastatic Tumors
Differential Diagnosis for
Pericardial Effusion







Infectious
Malignant
Autoimmune
Cardiomyopathy
Drug Induced
Cardiac
Constrictive
Pericarditis
 Radiation
 Trauma
 Metabolic:
Hypothyroidism
Uremia
OvarianHyperstimulationSyndrome
Pericardial Effusion
 All Causes of Pericardial Effusion Can
Also Cause Pleural Effusions.
 All Causes of Pericardial Disease Can
Also Include the Myocardium to Varying
Degrees. Termed Myopericarditis or
Perimyocarditis.
Infectious
Pericardial Effusion






Viral
Pyogenic/Bacterial
Fungal
Parasitic
Tuberculous
Any Infectious Agent Can Affect the
Pericardium
Viral Pericarditis
 Most Common Infectious Pericarditis
 Usually Cause Acute Pericarditis with: Fever, Rub,
Typical ECG Changes, Leukocytosis,
 3:1 Male to Female Ratio, Predominately in Young
Adults
 Usually Self Limited Resolving Within 2 Weeks
 Preceded by Upper Respiratory or GI Illness by 1-3
Weeks
 50% Have Recurrence Within 8 Months
 Common Viruses: Enteroviruses, Coxsackie A&B,
Adenovirus, Rhinovirus, Echovirus type 8, and
Influenza
 Diagnosis of Exclusion
Pyogenic/Bacterial Pericarditis
 Fulminant Course
 Symptoms Arise Over a Few Days and Usually Lead to
Tamponade and Sepsis
 Commonly Pneumococus, Staph, Strep
 Typically Associated with High Fever (Virtually All
Cases), Toxicity, Tachycardia, Rub
 Maybe More Insidious Course in the Elderly
 Usually Require Systemic Antibiotics and Pericardial
Drainage With Exploration
 In the Antibiotic Era Usually Associated with Dialysis,
Thoracic Surgery and Chemotherapy.
Fungal
Pericarditis
 Usually Occurs in Immunocompromised
 Histoplasma: Usually Young Males in Endemic
Areas, Often Benign Course Remitting
Spontaneously, May Have Mediastinal
Lymphadnopathy and Pleural Effusions
 Coccidiomycosis: Usually in Patients with
Widely Disseminated Infection
 Candida & Aspergillus: Opportunistic,
Necrotizing and Leading to Thrombosis
Parasitic Pericarditis
 Clinical Course Resembles that of
Pyogenic Pericarditis
 Residents or Travelers to Endemic Areas
 Usually Have an Identifiable Primary
Source i.e. Liver or Lung
 Eosinophillia
Primary Tumors
 75% Benign, 50% of Benign Tumors Are
Myxomas





25% Malignant
95% of Malignant Tumors Are Sarcomas
5% of Malignant Tumors Are Lymphomas
Symptoms Related to Location and Size
The Pathology of the Tumor Can Be
Speculated by Appearance on Imaging and
Anatomic Location
Myxomas




Occur in 3rd-6th Decades
Female Predominance 60-70%
80% Found in the Left Atrium
Presentation: Obstruction of Mitral or Tricuspid
Valve 67% (Occasionally Positional),
Embolization 29%, 15% of Cases Have Audible
Tumor Plop
 Constitutional Symptoms: Fever, Fatigue,
Weight Loss, Myalgias, and Arthralgias
 Not Commonly Associated With Pericardial
Effusion
Myxomas
 Echo Demonstrates Endocardial Mass,
Rarely May Be Intramural
 Treatment is Surgical Resection, Though
Myxoma May Recur 1-5%
 10% May Be Familial
Benign Papillary
Fibroelastomas
 2nd Most Common Benign Tumor
 Predominantly Affect Valves, Account for
75% of Valvular Tumors
 Often Asymptomatic, But May Present
with Dyspnea, Embolization, or Chest
Pain
 Visible By Echo as Mobile Endocardial
Mass
Other Benign Cardiac Tumors




All Are Rare
Rhabdomyomas: Most Present in Childhood
Fibromas: Most Present in Childhood
Hemangiomas: Have Characteristic Findings
on Imaging
 Lipomas: Have Characteristic Findings on
Imaging
 Teratomas: Have Characteristic Findings on
Imaging, Most Present in Childhood
Malignant Sarcomas
 Angiosarcomas: Most “Common”
Malignant Primary Cardiac Tumor
 Men:Women 3:1, 65-90% Have
Metastases at Presentation
 80% Occur In the Right Atrium
(Other Sarcomas Are Usually in the
Left Atrium)
Malignant Sarcomas
 Rhabdomyosarcoma: 2nd Most
“Common” Malignant Primary Cardiac
Tumor
 Can Occur at Any Age
 Most Have Aggressive Features Seen on
Imaging (Invasion of Local Structures)
Primary Cardiac Lymphomas
 By Far Most Commonly Occur in the
Right Atrium
 More Common in AIDS and
Immunocompromised Patients
 Most Are Fatal Shortly After Diagnosis
Metastatic Tumors
 20 Times More Common than Primary Tumors
 Lung, Breast, Leukemia, Lymphoma,
Melanoma, Kaposi’s Sarcoma
 Presenting Symptoms Based on Location of
Tumor, Usually Causes Pericardial Effusion
 If the Patient Is Symptomatic the Tumor Is
Virtually Always Visible on Echo, CT or MRI
 Most Patients Have Mediastinal
Lymphadnopathy
 Most Have Aggressive Features Seen on
Imaging (Invasion of Local Structures)
Autoimmune
Pericardial Effusion







Rheumatoid Arthritis
SLE
Scleroderma
Rheumatic Fever
Wegener’s Granulomatosis
Ankylosing Spondylitis
Inflammatory Bowel Disease
Cardiomyopathies







Ischemic
Dilated
Hypertrophic
Valvular
Hypertensive
Restrictive or Infiltrative
Inflammatory
Restrictive
Cardiomyopathy
 Excessively Rigid Ventricular Walls
Cause Diastolic Dysfunction
 Systolic Function Is Not Impaired
 Commonly Present with Dyspnea,
Fatigue and Chest Pain
 Commonly Associated with A-Fib
 Difficult to Distinguish Clinically from
Constrictive Pericarditis
Restrictive
Cardiomyopathy
 Storage Diseases
 Infiltrative
 Endomyocardial
Restrictive Cardiomyopathy
Inherited Storage Disorders
 Hemochromatosis: Deposition of Iron in Liver,
Pancreas, Gonads and Myocardium
 Fabry: Intracellular Accumulation of
Glycosphingolipids in the Skin, Kidneys and
Myocardium
 Gaucher: Accumulation of Cerebrosides in the Spleen,
Liver, Bone Marrow, Lymph Nodes, Brain and
Myocardium
 Glycogen Storage Diseases: Survival to Adulthood
Uncommon Except in Type III, Where Infiltration of the
Myocardium is Usually Not Clinically Relevant
Restrictive Cardiomyopathy
Infiltrative Disorders
 Amyloid
 Sarcoid
 Carcinoid Heart Disease: Serotonin
Producing Tumor Causing
Cutaneous Flushing, Diarrhea,
Bronchoconstriction and Right
Sided Endocardial Plaques
Composed of Fibrous Tissue
Restrictive Cardiomyopathy
Endocardial Fibrotic Diseases
 Endomyocardial Disease (Africa,
Eosinophilia)
 Loffler Endocarditis (Eosinophilia)
 Endomyocardial Fibrosis (Africa)
Myocarditis










Primary
Lymphocytic
Acute Rheumatic Fever
Eosinophilic
Lyme
Chagas
HIV
Drugs
Radiation
Giant Cell
Myocarditis
 Inflammation of the Myocardium Associated with Injury
to Myocytes
 Presents as an Acute Illness, Often Congestive Heart
Failure, Chest Pain and Fatigue
 Moderate Elevation of Cardiac Biomarkers,
Nonspecific ST-T Changes, Arrhythmias, Nonspecific
Echo
 Diagnosis by Endomyocardial Biopsy
Myocarditis
 Primary or Acute Myocarditis Associated with
Viral Infection (20 Viruses). Most Commonly
Enteroviruses (Coxsackie). Viral Etiology
Suggested by Antecedent Upper Respiratory
or GI Illness.
 Acute Viral Myocarditis is Associated with
Lymphocytic Infiltrate
Inflammatory Myocarditis
 Lymphocytic Myocarditis: Most Will Improve Over 1-6
Months, a Minority Will Fail to Clear a Cardiotropic
Virus or Develop Persistent Inflammation That Leads
to Chronic Cardiomyopathy, Heart Block or Ventricular
Arrhythmias.
 Myocarditis Treatment Trial: Prospective Randomized,
Double-Blind, Placebo-Controlled Trial of Prednisone
and Cyclosporine or Azathioprine for the Treatment of
Biopsy Proven Lymphocytic Myocarditis in Acute CHF.
There Was No Benefit from Immunosuppression.
 Immune Modulation for Acute Cardiomyopathy:
Evaluated the Role of IVIG and Found no Benefit.
 May Lead to Dilated Cardiomyopathy
Inflammatory Myocarditis
 Acute Rheumatic Fever: Pancarditis Occurring in 3% of
Untreated Streptococal A Pharyngeal Infections
 Hypersensitivity Myocarditis (Drug Induced):
Tricyclics, Penicillins, Antipsychotics, Present with
Rash & Fever
 Eosinophilic Myocarditis: Occurs in Conjunction with:
Hypereosinophilic Syndrome, Churg-Strauss
Syndrome & Loffler’s Endomyocardial Fibrosis.
Peripheral Eosinophilia
 Lyme Myocarditis: Borrelia burgdorferi, Often Develop
Heart Block or Arrhythmias,
 Chagas Cardiomyopathy: Trypanosoma cruzi
(Protozoan), Endemic to Central & South America
 HIV Myocarditis
Drug Induced Pericardial
Effusion






Procainamide
Hydralazine
Phenytoin
Isoniazide
Minoxidil
Methysergide\
ergot derivative
 Phenylbutazone/
NSAID






Anticoagulants
Cromolyn Sodium
Dantrolene
Thrombotics
Penicillin
Doxorubicin/
Adriamycin
 Cytoxan/
Cyclophosphamide
Cardiac
Pericardial Effusions
 Myocardial Infarction
 Postmyocardial Infarction “Dressler’s
Syndrome”
 Trauma
 Aortic Dissection with Hemorrhage into
Pericardial Space
 Postpericardiotomy
Constrictive Pericarditis
 No Pericardial Thickening Was Noted on
Imaging
 Few Case Reports of Constriction
Without Pericardial Thickening
 Would Not Account for Abnormal Left
Atrium Seen on Echo
Possible Etiologies for This
Case




Tuberculous Pericarditis
Cardiac Sarcoidosis
Cardiac Amyloidosis
Giant Cell Myocarditis
Tuberculous Pericarditis
 4-10% of All Acute Pericarditis is Caused
by TB (Reported up to 80% in Some 3rd
World Countries)
 1-4% of Patients with TB Have Pericardial
Involvement
 Etiology of 20% of Constrictive
Pericarditis
 Cases 93% of all Pericardial Effusions in
HIV Patients
Four Pathologic Stages of TB
Pericarditis
 I-Dry: Fibrin Deposition & Granulomatous
Reaction. Usually Clinically Silent
 II-Effusive: Serous Fluid Accumulation Caused
by Hypersensitivity to Tuberculoprotein and
Impaired Resorption
 III- Absorptive: Effusion Resolves and Fibrous
Tissue Replaces Granulomas, Pericardium
Thickens
 IV-Constrictive: Parietal Pericardial
Calcification
Presentation of Tuberculous
Pericarditis




Dyspnea 45-90%
Chest Pain 40-75%
Orthopnea 20-65%
Distant Heart Sounds
25-55%
 Rub 30-85%
 Cough 50-95%
 Fever 80-100%
Presentation of Tuberculous
Pericarditis
 50% of Patient Have Slowly Progressive
Insidious Presentation
 95% Have Cardiomegally, 30% Have
Active Pulmonary TB, 39-71% Have
Pleural Effusions L>R. Bilateral Pleural
Effusions More Common than Rub.
Tuberculous Pericarditis
 “Because of the variable and nonspecific
features of TB pericarditis, establishing
the diagnosis on clinical grounds alone
is impossible.” D.H. Spodick
 Diagnosis by Pericardial Fluid or Biopsy:
Positive AFB Smear, Culture, Caseating
Granulomas, TB DNA PCR
Treatment
Tuberculous Pericarditis
 Antibiotics: Isoniazid, Rifampin,
Pyrazinamide, Ethambutol
 Corticosteroids: Reduces Mortality and
Need for Subsequent Pericardiocentisis
Cardiac Sarcoidosis
 Causes Restrictive Cardiomyopathy
 Clinically Relevant in 5%, 25% Incidentally
Noted at Autopsy
 69% of Clinically Relevant Cardiac Sarcoidosis
Patients Have No Other Manifestations of the
Disease at Presentation
 Presentation: Complete Heart Block (Be
Suspicious in Young Patients With Complete
Heart Block), Ventricular Arrhythmia,
Congestive Heart Failure Systolic or Diastolic
Dysfunction
Cardiac Sarcoidosis
 Echo Usually Reveals Hyperechogenic Left
Ventricular Walls, May Develop Ventricular
Aneurysm From Myocardial Scar Tissue
 Diagnosis Based on Clinical Suspicion in a
Patient with Known Sarcoid or by
Endomyocardial Biopsy in a Patient with No
Evidence of Sarcoid in Other Organs. Biopsy
Consistent with Sarcoid 30% of Cases.
 Treat with Steroids
Cardiac Amyloidosis
 Causes Restrictive Cardiomyopathy
 Myocyte Destruction and Replacement
with Amyloid Fibrils (Beta Pleated
Sheets) Leading to Progressive
Thickening of the Ventricular Walls.
 More Common in Primary (AL)
Amyloidosis, a Plasma Cell Dyscrasia
Where Immunoglobulins Form Amyloid
Protein
Cardiac Amyloidosis
 EKG: Often Have Bundle Branch Block, Low
Voltage Despite Thick Ventricles, or A-Fib
 Most Patients with Amyloidosis, Even Those
with no Cardiac Symptoms, Have Abnormal
Echocardiograms with: Ventricular Wall
Thickening (70%), Isolated Septal Wall
Thickening (30%), Diastolic Dysfunction (57%),
Systolic Dysfunction (27%), Pericardial
Effusion (40%), Myocardial Sparkling Pattern in
2D (27%)
Cardiac Amyloidosis
 Diagnosis with Tissue Biopsy Revealing
Amyloidosis, Often Abdominal Fat Pad
 Prognosis Less Than 1 Year, Survival at 5
Years <5%
 Treatment: Primary Amyliodosis Limited
Benefit of Alkylating Agents
 Secondary Amyloidosis: Treat
Underlying Disease
Giant Cell Myocarditis
 Causes Inflammatory Cardiomyopathy
 Unknown Etiology
 Causes Progressive Left Ventricular Failure
and Arrhythmias, Over Weeks to Months
 Rare, 80 Cases Reported by 1997
 Average Age 43 (Infants to Elderly) Usually
Affects Otherwise Healthy Patients
 Equal Predominance of Men and Women
 90% Are Caucasian
Giant Cell Myocarditis
 Diagnosed by Endomyocardial Biopsy
Demonstrating: Diffuse Myocardial
Necrosis with Multinucleated Giant Cells
in the Absence of Sarcoid Like
Granuloma. Inflammatory Infiltrate in
Close Apposition to Myocyte Necrosis.
Negative Culture and Stains for Infection,
No Viral Particles on Electron
Microscopy.
Giant Cell Myocarditis
 75% Present with CHF, 25% with Ventricular
Arrhythmias, Sudden Cardiac Death (50%),
Heart Block, Diffuse ST-T Abnormalities on
EKG.
 May be Localized Rather Than Diffuse in
Earlier Stages. There Are Case Reports of
Giant Cell Myocarditis Affecting Only the Atria.
 20% Have Other Autoimmune Disease:
Hashimoto Thyroiditis, RA, MG, Takayasu
Arteritis, Alopecia, Vitiligo, Pernicious Anemia,
Crohn’s Disease, Ulcerative Colitis, ITP, Celiac
Disease
Giant Cell Myocarditis
 Survival 5.5 Months After Onset of Symptoms,
Normally Succumb to CHF or Arrhythmia
 Immunosuppresive Therapy with Corticosteroids,
Cyclosporin, Azathioprine Increases Survival to 12
Months, Case Reports of Dramatic Improvement with
Immunotherapy
 Cardiac Transplantation (with 25% recurrence), 71%
Survival at 5 Years
 The Giant Cell Myocarditis Treatment Trial and
Registry, Randomized Controlled Trial of T-Cell
Targeted Treatment with Muromonab-CD3 and
Cyclosporine
Possible Etiologies for This Case
 Tuberculous Pericarditis
 No Fever, No Exposure, Not Immunocompromized,
Would Not Explain Abnormal Atrium
 Cardiac Sarcoidosis
 No Evidence of Systemic Sarcoid, Normal Left
Ventricular Walls
 Cardiac Amyloidosis
 No Low Voltage EKG, No Ventricular Wall Thickening
 Giant Cell Myocarditis
 Time Course Is Consistant with Our Patient, Could
Account for Symptoms of CHF, Effusions, and
Abnormal Left Atrium
Diagnosis
 Giant Cell Myocarditis
 Diagnostic Test of Choice:
 Endomyocardial Biopsy
References













Spodick DH. The Pericardium. New York: Marcel Dekker; 1997
Braunwald E, Fauci AS. Harrison’s Textbook of Internal Medicine. McGraw-Hill; 2001
Up To Date, 2007
Garay S, Rom WN. Tuberculosis. Boston: Libble, Brown & CO; 1996
Hall HD, Hammar SP. Pulmonary Pathology. New York: Springer-Verlag; 1994
Roth JA, Ruckdeschel JC. Weisenburger, T. H. Thoracic Oncology. Philadelphia: W.B. Saunders
Company; 1995
Murphy JG, Lloyd MA. Mayo Clinic Cardiology. Rochester: Mayo Clinic Scientific Press; 2007
Zipes DP, Libby P, Bonow RO, Braunwald E. Braunwald’s Heart Disease. Philadelphia: Elsevier
Saunders; 2005
Silver MD, Gotlieb AI, Schoen FJ. Cardiovascular Pathology. Philadelphia: Churchill
Livingstone; 2001
Cooper LT, Berry GJ, et al: Idiopathic Giant-Cell Myocarditis. NE J Medicine, June, 1997
Frustaci A, Chimenti C, et al: Giant Cell Myocarditis, Responding to Immunosuppressive
Therapy. Chest, March, 2000
Cooper LT: Giant Cell Myocarditis: Diagnosis and Treatment. Herz, May, 2000
Rosenstein ED, Zucker MJ, et al: Giant Cell Myocarditis: Most Fatal of Autoimmune Diseases.
Seminars in Arthrithritis and Rheumatism, August, 2000
Special Thanks To:
 Dr. Erwin
 Dr. Starr
 Dr. Hurley