A 64-year-old woman presents with episodes of sudden chest pressure during exercise. She has no relevant past medical history, but her family history is significant for sudden cardiac death in both her mother and son. Electrophysiology reveals ventricular arrhythmias. She undergoes ventricular tachycardia ablation. Over the next three years, she develops worsening dyspnea on exertion with occasional episodes of exertional chest pain and fluid overload. She undergoes cardiac transplantation.

The explanted heart weighs 448 grams and measures 13.0 x 13.0 x 5.0 cm with a globular shape. The epicardial fat is increased while the coronary arteries are grossly normal. The right ventricle is markedly dilated, and the wall is thinned to 0.1 cm. The right ventricular endocardium shows diffuse fibrosis. Transmural fibrosis is present in the right ventricular posterior wall and interventricular septum, which measures 1.2 cm.

Master List of Diagnoses

  • Arrhythmogenic right ventricular cardiomyopathy
  • Atherosclerotic cardiovascular disease
  • Idiopathic cardiomyopathy
  • Rheumatic heart disease
  • Sarcoidosis
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 32, and is arrhythmogenic right ventricular cardiomyopathy of the heart.

Criteria for Diagnosis and Comments

Histologic sections show mostly fatty replacement of the right ventricular wall. The remaining cardiomyocytes show marked hypertrophy and surrounding fibrosis. There is no significant inflammatory infiltrate or granulomas. Congo red is negative for amyloid and there is no intercellular iron deposition. These findings are consistent with arrhythmogenic right ventricular cardiomyopathy (ARVC).

ARVC is a genetic disorder, typically autosomal dominant, which affects males more frequently than females. This disease usually manifests during adolescence or early adulthood. Due to variable penetrance, some patients may remain asymptomatic until late in life. The prevalence is 1 in 2,000 to 5,000 individuals. Patients usually present with palpitations or syncope. Due to fatty replacement of the ventricle wall, electrical conduction is impaired. Thus, patients are prone to arrhythmias and at risk for sudden cardiac death.

Most affected individuals have mutations in desmosomal genes, which are responsible for cellular adhesion. The following common genetic mutations show both autosomal dominant and recessive modes of inheritance: plakophilin-2 (PKP2, chromosome 12p11), desmoplakin (DSP, chromosome 6p24), plakoglobin (JUP, chromosome 17q21), and desmocollin-2 (DCS2, chromosome 18q12). Desmoglein-2 (DSG2, chromosome 18q12) is an autosomal dominant mutation. Autosomal recessive inheritance is associated with early onset and high penetrance.

Desmosomes are abundant in skin and heart tissues, which are susceptible to high frictional stress. Two autosomal recessive cardiocutaneous syndromes have been described. In Naxos disease (JUP mutation) and Carvajal disease (DSP mutation) patients present with ARVC, wooly hair, and palmoplantar keratosis.

There are three phases of ARVC. In the subclinical phase, patients have structural abnormalities but are asymptomatic. However, sudden cardiac death can still occur in this phase. The classic phase occurs when the patient manifests cardiac symptoms, either right ventricular arrhythmias or right ventricular failure with preserved left ventricular function. In the advanced phase, the patient develops end-stage cardiac disease characterized by biventricular dilation and heart failure. Left ventricular involvement can occur at any stage.

Electrocardiogram shows ventricular tachycardia, epsilon waves (sharp spike in ST segment), premature ventricular complexes of left bundle branch block morphology, or T-wave inversion in anterior leads. Echocardiography is used both for initial diagnosis and follow up. The right ventricle outflow tract shows diastolic dilation. Additionally, right ventricular wall abnormalities and disorganized trabeculations are also commonly observed. Contrast enhanced cardiac magnetic resonance imaging with gadolinium detects fatty tissue and intramyocardial fibrosis.

Grossly, right ventricular enlargement, increased right ventricular myocardial trabeculation, fibrofatty change, and scarring may be observed. Fatty replacement usually starts at the epicardium, and then eventually becomes transmural. Structural changes involve the right ventricular inflow tract, outflow tract or apex (the so-called “triangle of dysplasia”). Most cases also show left ventricular involvement, especially of the posterior lateral wall. However, the interventricular septum is usually spared. Aneurysms may form due to wall thinning.

Histological sections of the ventricle show mostly adipose tissue with interspersed myocytes and fibrosis. Focal inflammatory infiltrates may also be present. However, cardiac biopsy may be negative due to the segmental nature of this disease.

Atherosclerotic cardiovascular disease is characterized by coronary artery luminal narrowing and occlusion due to fibrofatty intimal plaques and superimposed thrombosis. This may lead to sudden asystole, arrhythmias, infarction and sudden death. Chronic disease causes subendocardial and interstitial fibrosis with dilated cardiomyopathy. There is more commonly left ventricular hypertrophy and dilatation.

Chronic rheumatic heart disease may develop as a complication of acute rheumatic fever (ARF) in susceptible individuals. Untreated Group A streptococcal pharyngeal infections or scarlet fever induces an autoimmune disorder with T cells and cytokines attacking the heart, joints, skin and brain due to antibody cross reactivity. ARF is most common in children, and may cause pancarditis, manifesting with dyspnea, heart murmurs, pericarditis, and heart failure. Myocardial perivascular Aschoff body consisting of lymphocytes and swollen macrophages (Anitschkow or Aschoff giant cells) develop. Repeated bouts of cardiac inflammation lead to chronic rheumatic disease with valvular, particularly mitral damage and patchy interstitial fibrosis.

Cardiac sarcoidosis also causes fibrosis which results in ventricular tachycardia and fibrillation. However, atrioventricular block is the most common arrhythmia. Unlike ARVC, the most commonly involved sites are the left ventricular free wall or the base of the intraventricular septum. Although non-caseating granulomas are diagnostic of sarcoidosis, the sensitivity of endomyocardial biopsy is low due to patchy involvement.

Idiopathic dilated cardiomyopathy is also characterized by ventricular wall thinning and myocyte loss. However, the left ventricle is uniformly dilated with progressive bi-ventricular involvement. The histologic picture is dominated by fibrosis and not fatty replacement of the ventricular wall.

Fatty myocardial infiltration alone can also be observed in obese and elderly patients. However, concomitant myocyte degeneration and fibrosis is pathologic.

Once ARVC is diagnosed, patients should avoid strenuous physical activity and competitive sports. Genetic screening of family members is important, since asymptomatic carriers are at risk for developing disease later in life. These patients should undergo lifetime clinical follow up. For symptomatic patients, anti-arrhythmic drug therapy such as beta-blockers can be helpful. Patients with unstable ventricular tachycardia, prior cardiac arrest, or unexplained syncope should undergo implantable cardioverter-defibrillator (ICD) placement to prevent sudden cardiac death. Catheter ablation is indicated for disease refractory to drugs and ICDs. Although this procedure is initially successful, patients frequently relapse. Cardiac transplantation may be indicated for advanced-phase patients.

Poor prognostic factors are right ventricular dilation and left ventricular involvement. Young patients may experience sudden cardiac death due to ventricular fibrillation. Older patients are more likely to experience ventricular tachycardia. Patients with ventricular dilation are at risk for developing mural thrombi with subsequent thromboembolic disorder.

  1. Which of the following is a gross characteristic of arrhythmogenic right ventricular cardiomyopathy (ARVC)?

    1. Biventricular hypertrophy
    2. Increased right ventricular myocardial trabeculation
    3. Left ventricular sparing
    4. Mitral valve fibrosis
    5. Septal fibrosis
  2. ARVC gene mutations most commonly involve which protein?

    1. Actin
    2. ATPase
    3. Desmosomes
    4. Integrins
    5. Intermediate filaments
  3. ARVC can also involve which of the following sites?

    1. Interventricular septum
    2. Left atrium
    3. Left ventricle
    4. Mitral valve
    5. Right atrium

References

  1. Basso C, Corrado D, Bauce B, Thiene G. Arrhythmogenic right ventricular cardiomyopathy. Circ Arrhythmia Electrophysiol. 2012;5(6):1233-1246.
  2. Basso C, Corrado D, Marcus FI, Nava A, Thiene G. Arrhythmogenic right ventricular cardiomyopathy. Lancet. 2009;373(9671):1289-1300.
  3. Kusano KF, Satomi K. Diagnosis and treatment of cardiac sarcoidosis. Heart. 2016;102(3):184-190.
  4. Sato T, Nishio H, Suzuki K. Identification of arrhythmogenic right ventricular cardiomyopathy-causing gene mutations in young sudden unexpected death autopsy cases. J Forensic Sci. 2015;60(2):457-461.
  5. Soler R, Rodríguez E, Remuiñán C, Bello MJ, Díaz A. Magnetic resonance imaging of primary cardiomyopathies. J Comput Assist Tomogr. 27(5):724-734.
  6. Zhang M, Tavora F, Oliveira JB, et al. PKP2 mutations in sudden death from arrhythmogenic right ventricular cardiomyopathy (ARVC) and sudden unexpected death with negative autopsy (SUDNA). Circ J. 2012;76(1):189-194.

Authors

Diana Murro Lin, MD
Surgical Pathology Resident
Rush University Medical Center
Chicago, IL

Vijaya B. Reddy, MD
Surgical Pathology Committee
Rush University Medical Center
Chicago, IL


Answer Key

  1. Increased right ventricular myocardial trabeculation (b)
  2. Desmosomes (c)
  3. Left ventricle (c)