Fernando Dominguez, MD
Pablo Garcia-Pavia, MD, PhD
Heart Failure and Inherited Cardiac Diseases Unit.
Hospital Universitario Puerta de Hierro, Madrid, Spain.
A 26-year old woman was admitted due to peripheral oedema and shortness of breath with minimal exertion, together with profuse sweating and cold extremities. The symptoms began 5 months before just after a gastrointestinal infection, and she noticed that her ability to perform physical activities progressively declined during this period.
The patient was Spanish and had no known family members from other countries. Moreover, she did not report recent travels to tropical or subtropical regions and her past medical history was unremarkable.
Upon arrival to the emergency department, the patient presented signs of low cardiac output with cold and clammy hands and legs, as well as oedema in the lower extremities. However, she was hemodnamically stable with a BP of 100/70 mmHg and oxygen saturation of 95% on room air. An ECG revealed a regular, narrow-complex, sinus rhythm at 80 bpm with flattened T waves in the inferolateral leads (Figure 1), and a chest x-ray showed mild signs of vascular redistribution (Figure 2). An echocardiogram was performed and evidenced a preserved systolic left ventricular function with normal wall thickness. Nonetheless, the patient presented a restrictive diastolic filling pattern, a mildly dilated and dysfunctional right ventricle and dilated atria, compatible with restrictive cardiomyopathy (Figure 3). Furthermore, the entire LV endocardium was delineated by a band of low attenuation which appeared brighter that the surrounding tissue (Figure 4), and the LV apex was akinetic and presented an attached mass which suggested the presence of an endocavitary thrombus (Figure 5). All these findings were confirmed by a CMR (Figure 6).
The patient was re-interrogated and denied family history of remarkable cardiac disease or sudden cardiac death, as well as recent expose to drugs or contact with animals. Contrary to what was expected, eosinophil count was normal (0.02 10E3/microL, 0.2%) and viral/ parasitic serologies were all negative.
In view of the patient’s poor prognosis due to the irreversibility of the disease and her disabling symptoms (peak oxygen consumption of 12.8 ml/kg/min, 6 min walking test of 350 m), she was listed for heart transplant and received a heart two months later. Currently, she is asymptomatic and in good health.
Figure 1. ECG showing sinus rhythm at 75bpm, narrow QRS complexes and unspecific T wave flattening in inferolateral leads
Figure 2. Anteroposterior chest x-ray with evidence of vascular redistribution
Figure 3. Doppler diastolic function assessment. E/A ratio: 2.2, E/e´ratio: 16.6. Compatible with restrictive filling pattern
Figure 4. Transtoracic echocardiogram. Parasternal short axis view.at papillary muscle level. Subendocardial bright band suggestive of fibrosis
Figure 5. Transtoracic echocardiogram. 4 chamber view. Mass attached to the apex suggestive of thrombus (white arrow)
Figure 6. CMR. 4 chamber view. Extensive areas of subendocardial late gadolinium enhancement affecting the LV. Thrombus in the apical septum (White arrow).
Solutions in next case
By Alexandros Protonotarios MD, Adalena Tsatsopoulou MD and Aris Anastasakis MD, PhD
The diagnosis of Arrhythmogenic Cardiomyopathy (ACM/ALVC) was based on 4 minor criteria:
Left ventricular involvement and the extensive fibrosis mainly subepicardial is characteristic for myocarditis but also in familial cases as ACM/ALVC. (1-3) The diagnosis of certainty and the differential diagnosis of myocarditis and ACM/ALVC is based on endomyocardial biopsy.
Implantation of an ICD was suggested due to family history, genetic analysis result and left ventricular involvement which is an indication of increased risk for sudden death. A week before the programmed ICD implantation, he died suddenly “due to emotional stress”.
On postmortem, extensive involvement of the left ventricular wall (Fig 5, arrows) with myocyte degeneration and fibrous and fatty replacement was observed (Fig 6). The right ventricle was not involved.
Figure 6: LV histology
Genetic investigation of the family revealed:
Mutation in Desmoplakin gene: Trp180Stop, NP_004406.2:p.W180* (Fig 7,8)
Carefully looking back at the history of the family, the girl who died suddenly during sleep presented mild palmoplantar keratosis. The grandfather who died young (father-side) also had palmoplantar keratosis.
The diagnosis of ACM/ARVC is based on criteria derived from arrhythmias, electrocardiographic changes, structural/functional abnormalities of the right ventricle on two-dimensional echocardiography or cardiac magnetic resonance, family history/genetics and morphometric histopathological pattern (1). Left ventricular involvement is a common finding sometimes being predominant particularly in association with desmoplakin mutations potentially with an early and worse arrhythmic outcome (2, 3). However, detectable markers for left ventricular involvement are not adequately represented even amongst the latest revision of the diagnostic criteria ( 1).
This is why in cases in whom left ventricular alterations predominate, the diagnosis might be missed although they are at increased risk, since involvement of the left ventricle in ACM has long been considered as a risk factor for sudden cardiac death.(4-8)
Cutaneous involvement of the type of palmoplantar keratoderma and woolly hair is always a warning sign of cardiac involvement requiring targeted cardiac investigation ( 4).
Mutations in desmoplakin have been associated with early involvement of the left ventricle, which shows usually mild skin alterations which, although palpable might be easily missed with eye only inspection.(4,8-10).
Presentation of ARVC as myocarditis with troponin elevation has been described ( 5,6). Histopathology of myocardium quite commonly reveales inflammatory infiltrates ( 7).
Biopsy-proven acute myocarditis may be associated with an active phase of ACM that leads to changes in phenotype and abrupt progression of the disease. However, the pathogenetic significance of virus-negative myocarditis in ACM is unclear, and it may represent myocarditis mimicking ACM, myocarditis associated with ACM, or a form of genetically determined myocarditis., e.g. ACM mutations may increase the susceptibility to myocarditis.(3,5-7,9-12)
Application of molecular genetic screening in the family for the causative mutation is essential for the protection of family members(10-11).
Caforio ALP, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, Fu M, Heliö T, Heymans S, Jahns R, Klingel K, Linhart A, Maisch B, McKenna W J, Mogensen J, Pinto Y, Ristic A, Schultheiss HP, Hubert SeggewissH, TavazziL, Thiene G, Yilmaz A, Charron P, ElliottPM. Current state of knowledge on aetiology, diagnosis, management and therapy of myocarditis. A Position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 20132013; 34:2636-48
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