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Familial hypertrophic cardiomyopathy: malignant and variable phenotypes.

A whole family with inherited cardiomyopathy.
Myocardial Disease


The proband (IV:5) is a 38-year-old female who had the first diagnosis of hypertrophic cardiomyopathy at the age of 10 years. She has been asymptomatic for more than 20 years.

Arrhythmic phase of the disease

Few years after the diagnosis, she was given Verapamil therapy to prevent further worsening of the hypertrophy and development of symptoms. In September 2003 she suffered the first episode of atrial flutter that was successfully treated with external cardioversion. Further episodes of atrial fibrillation and flutter recurred  in the following years all repeatedly treated with external cardioversion. Amiodarone treatment was started after one of the several arrhythmias episodes and withdrawn due to hyatrogenic hyperthyroidism. After atrial ablation in 2006 and an ICD implantation, the atrial flutter recurred in February 2007. Since then, the atrial arrhythmia was chronic.

Heart failure phase
The onset of mild dyspnoea on efforts and asthenia dates first month of 2007; in January 2008 the patient complained about thoracic pain: she underwent coronary angiography that showed normal coronary arteries.

She was first addressed to our Centre in June 2008. She was in functional NYHA class III-IV. We performed cardiologic evaluation, ECG registration, Holter monitoring, echocardiogram and genetic counselling and blood sample collection for molecular analysis.

Cardiologic Visit:
Arrhythmic heart sounds, apical systolic murmur. Fine crepitations on pulmonary bases, bilaterally. Hepatomegaly. Absence of leg swelling; presence of jugular turgor.

ECG:
Atrial flutter with variable conduction to ventricles; mean ventricular rate of 60 beats/min; normal QRS axis; absence of indices of myocardial hypertrophy (negative Cornell and Sokolow-Lyon criteria).


Atrial flutter with variable conduction to ventricles.

Holter Monitoring:
atrial fibrillation/flutter over the 24 hours of recording. Single recording of 13 consecutive beats of aberrant conduction to ventricles. Absence of pauses; few PM interventions. In the report the patient described dyspnoea and fatigue which corresponded to the recording of increased heart rate.

Echocardiogram:
- basal segments: interventricular septum thickness 10 mm; posterior wall 14 mm; inferior wall 15 mm;
- distal segments: inferior and posterior wall thickness, 26 mm;
- increased thickness of the right ventricular free wall;
- ejection fraction: 45-50%; decreased end-diastolic left ventricular volume (32 ml)
- biatral enlargement; presence of restrictive mitral inflow pattern (E/A 2,78, deceleration time 120 msec);
- Estimated pulmonary arterial pressure in systole: 35-40 mmHg;
- Hepatic veins and inferior vena cava: congested

Panel A and B: short axis views, basal and distal segments respectively. Worth noticing is the mild hypertrophy in the basal inferior and posterior segments, whereas in the apical segments the hypertrophy is much more evident. Panel C: long-axis view of the left ventricle. The severe hypertrophy of the posterior wall begins after the papillary muscles. Panel D: apical view showing the hypertrophy of distal segments and evidence of spontaneous smoke effect in the ventricle.

Biochemistry:             
                                            Result:                  Normal range:
- B-type Natriuretic Peptide     367 pg/ml              0-50
- Lactic Dehydrogenase          622 U/L                 230-460
- Sodium                               131 mEq/L             135-153
- Troponin I                             0.123 ng/ml           0-0.04

Other biochemical parameters were normal (total serum CPK and CK-MB, creatinine, Lactic Acid, Myoglobin, haemochrome, C-reactive Proteine, ErytroSedimentation Rate).

The patient was admitted to the hospital August 2008 to optimize pharmacological treatment and to restore hemodynamics. She was put on the waiting list for heart transplantation. Heart transplantation was performed on 30th December 2008.

Family History and Screening:
The first step of the family screening study included the family nucleus from III:7 (within the blue line area. We traced medical records of the deceased maternal grand-mother (II:2), documenting that she was affected but reported data were descriptive only
The proband is the fourth offspring of non-consanguineous parents, with unaffected father and proven, affected mother. The proband (IV:5) is the fourth of six sibs. A younger brother died suddenly at the age of 28 years (IV:3); an older sister underwent heart transplantation for HCM at the age of 56 years (IV:2); one younger brother is affected by HCM (IV:7). Two sibs (IV:4, IV:6) are unaffected.


The proband is mother of a 9-year-old boy (V:5) who is affected by HCM (z score of the left ventricular wall thickness 4,05 with the exception of distal posterior wall that showed z score of 8,74) with normal mitral inflow pattern (Figure A). The ECG of the boy (Figure B) showed abnormal  T waves (negative T waves in the inferior leads) but  no left ventricular hypertrophy.


 

Figure A - Normal mitral inflow pattern in the 9-year-old boy (V:5) with hypertrophic cardiomyopathy.

 


Figure B - Electrocardiographic examination of the 9-year-old son of the proband. No ECG criteria (Sokolow-Lyon and Cornell) for left ventricular hypertrophy. Negative T waves in inferior and lateral leads. Early repolarization  on precordial leads (C2 to C4).

 

 


The whole family includes 41 relatives (excluding healthy siblings of healthy members), of which 23 are affected. Among affected relatives, 14 died prematurely: of these, 12 died suddenly (aged between 8 and 63 years), one died of heart failure at the age of 56 years and one woman died at childbirth at the age of 25. One patient underwent ICD implantation after syncope at the age of 16 years.

Questions:

1) Could you hypothesise what is the causative gene of the disease in this family or indicate genes that should be screened with priority??
2) Figure 1: suppose you see this ECG without having the ECHO data: would you suspect an HCM? If yes, why?

Answer:
(This material is original; it has not previously published and is part of a research on Hypertrophic Cardiomyopathies supported by funds from Cariplo Foundation and Health Ministry granted to EA).

Further family investigation:
The maternal cousin  (relative III:3) of the proband (IV:5) was contributory for the final diagnosis (Figure 1, green arrow).

The maternal cousin  (relative III:3) of the proband (IV:5) was contributory for the final diagnosis (Figure 1, green arrow).


This patient came to our attention at the age of 56 years with the following history and clinical records:

  • RCM diagnosis – age: 46 years;
  • Atrial flutter – age: 47 years
  • ICD implantation – age 48 years  (no appropriate ICD interventions documented during a 10-year follow-up).

Serial echocardiography studies (up to 2008): normal wall thickness (septum,  z score -1.0 to 0,75), biatrial dilation, restrictive LV filling pattern.

On more recent examinations:
Severe intraventricular and intra-atrial spontaneous smoke (low flow due to the increased ventricular filling pressures) (Figure 2).

Symptoms
In the last two years she complained frequent episodes of congestive heart failure with hepatomegaly, pleural effusion, peritoneal effusion mild leg oedema.

Endomyocardial biopsy (EMB)
Interstitial and perivascular fibrosis; myocyte disarray; both normal and hypertrophic cardiomyocites.

The patient underwent heart transplantation at the age of 57 years.

Figure 2. Panel A: evidence of spontaneous intra-cardiac smoke in restrictive cardiomyopathy pattern (biatrial dilation, normal ventricular chamber size, normal ventricular wall thickness). Panel B: Pulsed Wave Doppler shows restrictive mitral inflow pattern.

Considerations on the genetic basis of RCM
Restrictive cardiomyopathy is a rare cardiomyopathy clinically characterized by impaired relaxation and abnormal left ventricular filling, dilation of both atria and absence of significant left ventricular hypertrophy [1-3]. The genetic basis of primary restrictive cardiomyopathy includes mutations of the following genes: alpha cardiac actin [4], desmin [5,6] Troponin I [3,4] and Troponin T [4,7].

Results of genetic testing
The molecular analysis identified the p.Leu144Gln mutation of the Troponin I gene in the proband, her son, and the cousin who also underwent heart transplantation. The extension of genetic testing to live patients of the family confirmed the segregation of the mutation with the phenotype. Other sarcomeric genes tested negative.

TNNI3-associated phenotypes
TNNI3 patients may show pure RCM and HCM with or without restrictive pattern. Different phenotypes may coexist in the same family [4,8,9]. In the present family, as in other families observed in our centre with TNNI3-related cardiomyopathy, only the presence of a pure RCM without conduction disease in at least one member of the family seems to predict mutations of this gene. Differential clinical diagnosis includes pure restrictive phenotype caused by mutations of the Desmin gene, which are however characterized by the presence of atrioventricular block preceding the onset of restrictive haemodynamics and in some case, of clinically overt myopathy or increased sCPK. [6].
 

Conclusion:

Although genetic testing was performed only in living members of the family, the clinical records of deceased relatives documented HCM or SD due to cardiomyopathy. The phenotypes associated with Troponin I gene defects (RCM, HCM with or without restriction pattern) seem to be rather malignant as shown by the family history: 12 affected relatives died suddenly, one patient underwent ICD implantation and three underwent heart transplantation.

Three phenotypes may coexist in families with cardiomyopathy caused by Troponin I gene mutations:

  1. Hypertrophic cardiomyopathy with impaired diastolic filling without evolution through restrictive haemodynamics over 10 years (the impairment of diastolic function could apper later on in the course of the natural history of  the disease);
  2. Hypertrophic cardiomyopathy with restrictive haemodynamics
  3. Pure restrictive phenotype with normal wall thickness, severe biatrial enlargement, normal ventricular dimension, restrictive mitral inflow pattern.

References


1. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European society of cardiology working group on myocardial and pericardial diseases. Eur Heart J 2008;29:270-6
2. Richardson P, McKenna W, Bristow M, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation. 1996;93:841-2
3. Kubo T, Gimeno JR, Bahl A, et al. Prevalence, clinical significance, and genetic basis of hypertrophic cardiomyopathy with restrictive phenotype. J Am Coll Cardiol. 2007;49:2419-26
4. Kaski JP, Syrris P, Burch M, et al. Idiopathic Restrictive Cardiomyopathy in Children is Caused by Mutations in Cardiac Sarcomere Protein Genes. Heart. 2008 in press (PMID: 18467357)
5. Arbustini E, Morbini P, Grasso M, et al. Restrictive cardiomyopathy, atrioventricular block and mild to subclinical myopathy in patients with desmin-immunoreactive material deposits. J Am Coll Cardiol. 1998;31:645-53
6. Arbustini E, Pasotti M, Pilotto A, et al. Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects. Eur J Heart Fail. 2006;8:477-83
7. Menon S, Michels V, Pellikka P, et al. Cardiac troponin T mutation in familial cardiomyopathy with variable remodeling and restrictive physiology. Clin Genet. 2008 in press (PMID: 18651846)
8. Mogensen J, Kubo T, Duque M, et al. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest. 2003;111:209-16. Erratum in: J Clin Invest. 2003;111:925
9. Mogensen J, Arbustini E. Restrictive cardiomyopathy. Curr Opin Cardiol. 2009;24:214-20.
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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