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Refining the diagnosis of “Restrictive Cardiomyopathy”: an illustrative case

The Clinical Case of the Month: January 2009

Case Presentation:

A 50-year-old Caucasian Italian woman with a 2-year history of congestive heart failure was referred to our institutional heart transplantation programme. She was carrying a DDD pacemaker. Initially, she had been implanted with a VVI pacemaker at 35 years of age following a period of asthenia and exercise dyspnoea, which had led to a diagnosis of complete atrioventricular block. At 42 years of age, she was found to have type II diabetes mellitus. The patient’s clinical history had otherwise been uneventful until progressively worsening congestive heart failure (from 48 years of age), with gradual onset of asthenia, exercise dyspnoea and leg oedema.

Myocardial Disease


At family anamnesis, it emerged that the patient’s mother had married a first-degree cousin who died suddenly while suffering from an undefined heart disease. Furthermore, one of the patient’s brothers had been implanted with a pacemaker (for unknown reasons) while living in South America.

Before reaching our centre, the patient had been evaluated with coronary arteriography, which was unremarkable. She had also been submitted to a peripheral muscle biopsy due to suspected systemic disease: it was reported that histology had not revealed any specific findings. At the time of referral to our institution, the clinical picture was characterized by leg oedema, moderately enlarged liver and raised central venous pressure (>10 mmHg). Her DDD pacemaker was working normally (Fig. 1).


Regular pacemaker rhythm is present
Fig. 1: Regular pacemaker rhythm is present

Two-dimensional echocardiography disclosed biatrial enlargement with normal ventricular volumes and conserved left ventricular ejection fraction (Fig. 2A); the inferior vena cava was enlarged (Fig. 2B) and failed to show any respiratory variations in diameter.

Two-dimensional echocardiogram in 4-chamber     Two-dimensional echocardiogram in 4-chamber and subcostal

Fig. 2: Two-dimensional echocardiogram in 4-chamber (A) and subcostal (B) views. Biatrial enlargement coexists with normal ventricular volumes. Inferior vena cava is markedly enlarged.

Transmitral Doppler echocardiography showed shortened E-wave deceleration time (100 msec). On cardiopulmonary exercise testing, peak VO2 was severely restricted (10.5 ml/Kg, 36% of the theoretical value). Routine laboratory tests were unremarkable. Antidiabetic therapy was optimized and intravenous diuretics and antialdosterones were initiated. Right heart catheterisation and endomyocardial biopsy were conducted.

Right heart catheterisation showed:
- Mean capillary wedge pressure, 25 mmHg.
- Right atrial mean pressure, 16  mmHg.
- Early diastolic right ventricular pressure, 5 mmHg.
- End diastolic right ventricular pressure, 16 mmHg.
- Dip plateau morphology of the right ventricular diastolic pressure tracing.
- Pulmonary artery pressure, 55/16/29 mmHg.
- Cardiac index, 1.19 L/min/m2.

At the histological level (Fig. 3), endomyocardial biopsy showed only diffuse, moderate fibrosis without any sign of infiltrative myocardial disease (including amyloid infiltration).


Myocardial biopsy findings

Fig. 3: Myocardial biopsy findings Histological examination shows diffuse endomyocardial and perimyocytic fibrosis (blue at Mallory thricrome staining)

Answers:

At this point, the only possible (provisional) diagnosis is idiopathic restrictive cardiomyopthy (RCM), based on:

  • Restrictive pathophysiology (normal ventricular volumes and left ventricular ejection fraction; increased filling pressure; dip plateau morphology of the right ventricular pressure tracing).
  • No apparent sign of specific aetiology (in particular, infiltrative/storage disease).

Nevertheless, some clues could orient the diagnostic work-up towards a more precise diagnosis:

  • Famililiality seems highly probable.
  • Coexistence of RCM and advanced atrioventricular block at an early age.
  • These considerations prompted us to reconstruct a complete pedigree, based on clinical history and direct clinical/instrumental examination of living relatives. The pedigree indicated a recessive autosomal familial disease within the context of consanguineous intermarriage. The observation of an apparently idiopathic RCM in a familial context suggested the hypothesis of desmin-related cardiomyopathy. To evaluate this hypothesis, we performed ultrastructural analysis of the myocardial biopsy material and conducted DNA analysis to identify the desmin gene (DES) mutation. Electron microscopy (Fig. 4) demonstrated intracellular accumulation of material compatible with desmin (Fig. 4).

Fig. 4: electron microscopy discloses typical, desmin-related,Electron microscopy discloses typical, desmin-related, granulo-filamentous, intracellular material
granulo-filamentous, intracellular material

DNA analysis revealed that the patient was a homozygous carrier of a known pathogenetic mutation (R16C) in the DES gene. Other members of the large family agreed to DNA analysis: as many as 13 first or second degree relatives turned out to be phenotypically unaffected heterozygous carriers of the R16C mutation.

Final diagnosis: Desmin-related familial cardiomyopathy

Comments

In many cases, RCM should nowadays no longer be considered a final diagnosis, but rather a starting point for further assessment. At each diagnostic step, the clinician should be prepared to recognise highly specific (though not necessarily sensitive) signs that can provide clues for the true final diagnosis. In the present case, the combination of RCM and atrioventricular block  in a young patient orients the diagnostic work-up.

Desmin is a polypeptide that normally aggregates to form “intermediate filaments” (whose diameter [8–10 nm] is intermediate between that of the myosin filaments and actin filaments) that normally provide link Z disks between adjacent myofibrils, the sarcolemma and nuclear membranes. Pathogenic mutations in the desmin gene give rise to intramyocellular desmin accumulation. The resulting clinical phenotypes are variable, but commonly include systemic myopathies with or without cardiomyopathy. Nevertheless, restrictive (or dilated) without clinically evident peripheral myopathy is also possible. The restrictive phenotype is typically accompanied by atrioventricular blocks. In the context of familial transmission, this combination of features must raise a strong suspicion of desminopathy.

The absence of specific histological alterations in the peripheral muscle and endomyocardial biopsies deserves some comment. Whereas light microscopy assessment of endomyocardial tissue shows nonspecific features, electron microscopy regularly reveals the typical desmin-related granulo-filamentous material which is diagnostic for desmin-related cardiomyopathy. The ultrastructural appearance of the deposits is identical in the myocardium and peripheral muscle. This knowledge is especially important for patients undergoing endomyocardial biopsy: in such cases, an incomplete investigation could lead to a missed diagnosis. Cardiologists and pathologists should be aware of these potential pitfalls.

Conclusion:

Since desmin-related RCM is a likely diagnosis in patients with RCM accompanied by atrioventricular block cardiologists should specifically ask pathologists to perform electron microscopy assessment of their biopsy samples.

Notes to editor


By Prof. C. Rapezzi, Dr. O. Leone and Prof. E. Arbustini
Institute of Cardiology, University of Bologna and S. Orsola-Malpighi Hospital, Bologna, and Centre for Inherited Cardiovascular Diseases, Molecular Diagnostic Laboratory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.