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.
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.
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).
Fig. 3: Myocardial biopsy findings Histological examination shows diffuse endomyocardial and perimyocytic fibrosis (blue at Mallory thricrome staining)
At this point, the only possible (provisional) diagnosis is idiopathic restrictive cardiomyopthy (RCM), based on:
Nevertheless, some clues could orient the diagnostic work-up towards a more precise diagnosis:
Fig. 4: electron microscopy discloses typical, desmin-related,
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
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.
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