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Misleading phenotype or biased cardiologists?

First clinical evaluation at our centre

A 20-year-old Caucasoid male, a soccer non-competitive athlete was referred to our attention for recent onset exertion dyspnoea and palpitations. He was suspected to be affected by Marfan syndrome (MFS). He was tall (height 190 cm) and weighted 62 Kg. The prior clinical history was negative.

Myocardial Disease


The cardiologic evaluation documented a mild pansystolic murmur consistent with mitral regurgitation.  The ECG showed sinus rhythm, HR 67 beats/min, and normal repolarisation pattern (Fig. 1). Two-dimensional echocardiography disclosed mitral valve prolapse with mixomatous degeneration of the mitral leaflets associated with mild mitral regurgitation; the aortic root diameter was at the upper limit of the normal range (aortic root ratio 1.12; z-score 1.62) (fig. 2). Left ventricular dimensions and function were within the normal range.  Left atrium and transmitral blood flow were normal. Holter monitoring showed short episodes of paroxystic atrial fibrillation.

Figure 1: The ECG showed sinus rhythm, HR 67 beats/min, and normal repolarisation pattern 

Fig 2: The aortic root diameter was at the upper limit of the normal range (aortic root ratio 1.12; z-score 1.62)

The orthopaedic evaluation showed:
• pes planus,
• scoliosis <20°. 
The patient did not show other skeletal traits suggestive for MFS.
The ophthalmologist evaluation excluded ocular traits.
The lumbosacral MRI documented dural ectasia.

Family history and evaluation (Fig. 3)

Mother and maternal lineage
br /> The mother showed mitral valve prolapse with moderate to severe mitral regurgitation, mild left ventricular dilation and preserved left ventricular function. Her skeletal, and ocular phenotype did not show traits suggestive for MFS. The grandmother died suddenly at the age of 62 years; autopsy was not performed. Other maternal relatives did not show cardiovascular abnormalities and none of them had positive history for cardiovascular diseases.

Father and paternal lineage

The father died suddenly at the age of 50 years. He was described as tall and thin and using glasses since young age. No picture was available. From the narrative of the proband, the father had complained, one month before death, non-otherwise specified cardiac “problems”.  Two paternal uncles (52- and 48-year-old) also died suddenly. Their offsprings were referred to be healthy.  One additional uncle was described as healthy as were their offspring. The paternal grandmother also died suddenly at the age of 62 years: she was known to suffer cardiovascular “problems”. The paternal relatives who died suddenly did not undergo autopsy.

Sibs

A 22-year-old brother underwent clinical evaluation that documented the absence of extra cardiac traits suggestive for MFS, and ECG and echocardiographic study that showed normal parameters.

Fig 3: Family history and evaluation

We excluded Marfan syndrome in the proband on the basis of Ghent criteria (Ref. 1). Independently on the absence of major criteria for MFS, the paternal family history with several sudden deaths, the symptoms, and the short episode of AF deserved further clinical evaluation and monitoring. We suggested medical treatment and proposed beta-blocker. He refused to take drugs and decided to come for further controls on his own scheduling. We did not have further information for about two years, when the patient called our centre and asked for a clinical control.

Second clinical evaluation at our centre 18 months later.

The patient came with clinical reports documenting that one year after our first evaluation, he had a persistent episode of atrial fibrillation that had been successfully controlled with intravenous propafenone. He was not given treatments. Six months after this episode, he suffered a presyncope and was admitted to the local hospital. From the clinical reports, the arterial blood pressure was 95/65 mmHg and oxygen saturation was 98%. ECG showed atrium fibrillation (Fig. 4). Routine biochemical tests were negative. The TEE excluded sources of thromboembolism. He was given anticoagulants and addressed to our centre.


Fig 4: ECG showed atrium fibrillation

A TTE study confirmed previous data: in particular, left atrium was normal and there were no sources of thrombolembolism. He underwent successful external electric cardioversion. A few days later, the Holter monitoring documented sinus rhythm (mean heart rate 55 beats/min, range 37-122); isolated PVC (n=30) one episode of non-sustained ventricular tachycardia (fig. 5); isolated and repetitive atrial extrasystoles (maximum 5 beats). He was discharged from the hospital and given beta-blocker therapy (bisoprolol 1.25 mg/day).

Fig 5: the Holter monitoring documented sinus rhythm (mean heart rate 55 beats/min, range 37-122); isolated PVC (n=30) one episo

We repeated an ECG Holter monitoring that confirmed the sinus rhythm interrupted by diurnal and nocturnal short phases of junctional rhythm and documented three episodes of non-sustained ventricular tachycardia (max 10 beats).
Based on these results, we proposed the electrophysiological study that showed:

  • no inducible of sustained ventricular arrhythmias;
  • mild delay of sub-hissian conduction with regular sinus function;
  • absence of AVB;
  • induction of reproducible right atrial tachycardia
  • induction of typical atrial flutter with fast evolution to atrial fibrillation

A cardiac MR demonstrated increased left ventricular diastolic volume (107 ml/mq) with normal ejection fraction (LVEF = 51%), normal wall thicknesses and absence of late gadolinium enhancement. 

Would you suggest further diagnostic investigation?
Do you think that genetic testing for MFS is appropriate?
What is your diagnostic hypothesis, based on the available clinical data?

1. the severe paternal family history of sudden cardiac death
2. the documented short episodes of NSVT in the proband
3. the mild delay of subhissian conduction recorded at the EP study

Due to the difficult clinical orientation, we asked the family to trace the medical records of the father and eventually of other deceased relatives, and to address this material to our attention.

Diagnosis, case resolution and treatment

Examination of the paternal clinical reports.

The paternal medical records reported that one month before dying suddenly the father had undergone pacemaker implantation for brady-tachy syndrome and the echocardiographic study had shown mild left ventricular dilation and dysfunction (LVEDD = 60 mm; LVEF = 40%). The coronary angiography was not performed. The discharge diagnosis was early DCM associated with chronic AF.

Considerations and diagnostic resolution

When we had to decide how to progress with the diagnostic work-up, the key data were:
1. the severe paternal family history of sudden cardiac death
2. the paternal conduction disease and dilated cardiomyopathy
3. the paternal SD despite PM
4. the documented short episodes of NSVT
5. the mild delay of subhissian conduction recorded at the EP study.

We proposed the analysis of LMNA that tested positive.

ICD implantation

In the post-test counselling, we informed the patient about our current knowledge on clinical phenotypes associated with LMNA gene mutations, the family and personal data as warning indicators of a potential risk of events, and explained the possible treatments, both medical and ICD. In particular, we suggested the ICD implantation for primary prevention. The patient refused the proposal of the ICD (he signed the refusal form) and accepted medical treatment with bisoprolol 5mg/day.
The patient regularly come to our attention twice a year and is asymptomatic four years after onset of symptoms. Serial ECG Holter monitoring did not show further episodes of NSVT and AF. The echocardiographic parameters are stable.

Conclusion:

Despite the clinical stability and wellness of the patient, the data reported in the literature about the risk of sudden death in LMNA mutation carriers, independently on LV dysfunction and dilatation (1-4) and the malignant family history raise the question on to whether the patient is really protected from life-threatening ventricular arrhythmias. Should we further encourage ICD implantation?

References


DePaepe A, Dietz HC, Devereux RB, Hennekem R, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62:417–
Pasotti M, Klersy C, Pilotto A, Marziliano N, Rapezzi C, Serio A, Mannarino S, Gambarin F, Favalli V, Grasso M, Agozzino M, Campana C, Gavazzi A, Febo O, Marini M, Landolina M, Mortara A, Piccolo G, Viganò M, Tavazzi L, Arbustini E. J Am Coll Cardiol. 2008;52:1250-60
van Berlo JH, de Voogt WG, van der Kooi AJ, van Tintelen JP, Bonne G, Yaou RB, Duboc D, Rossenbacker T, Heidbüchel H, de Visser M, Crijns HJ, Pinto YM. J Mol Med. 2005 ;83:79-83
Meune C, Van Berlo JH, Anselme F, Bonne G, Pinto YM, Duboc D. N Engl J Med. 2006;354:209-10.
Arbustini E, Pilotto A, Repetto A, Grasso M, Negri A, Diegoli M, Campana C, Scelsi L, Baldini E, Gavazzi A, Tavazzi L. J Am Coll Cardiol. 2002;39:981-90

Notes to editor


Presented by Michele Pasotti, Fabiana Isabella Gambarin, Alessandra Serio, Luigi Tavazzi*, Eloisa Arbustini
Centre for Inherited Cardiovascular Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia and *GVM Care and Research, Cotignola (Ravenna), 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.

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