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Magnetic resonance imaging confirmed systolic impairment with global left ventricular hypoki-nesia, which was more prominent in the apical segments. Right ventricle was not dilated and had normal systolic function. Gadolinium sequences revealed no late enhancement areas. Troponins, CK and CK-MB were normal. Rest of routine blood test were unremarkable (including ferritin and thyroid function). Coronary CT scan showed normal coronaries. Patient underwent a Tilt test which was positive (vasodepressive response) producing symptoms that led to consultation. 24 hours ECG-Holter monitoring was normal. There was no prior history of infection or febrile episode within the last 6 months and patient was not on any medication at the time of the consultation. Endomyocardial biopsy was discussed but finally not considered at the time. Bisoprolol and ramipril were initiated with good tolerance and the patient was discharged with an appointment to be seen in the outpatient cardiomyopathy clinic for further examinations and follow-up.
Family study led to the following findings. A paternal uncle had been diagnosed with hypertrophic cardiomyopathy with typical asymmetrical septal hypertrophy phenotype (maximal left ventricular hypertrophy of 20 mm and severe dynamic obstruction). Father was found to have mild left ventricular hypertrophy of 12mm which was considered secondary to longstanding hypertension, and his ECG was unremarkable (figure 3A). Mother had minor ECG abnormalities with peaked P wave and late R transition in precordial leads, with normal echocardiogram (figure 3C). Study of the maternal side of the family (5 sisters and the grandmother) revealed some abnormalities on the ECGs. Maternal aunts tend to have low voltage QRS and flat T waves throughout (figure 3D). Echocardiogram in the maternal aunts were normal. Maternal grandmother´s ECG demonstrated negative T waves laterally and inferiorly (figure 3E).
Echocardiogram of the 79 years old grandmother who always was asymptomatic, showed moder-ate left ventricular systolic impairment (EF 45%) with normal size left ventricular diameters (EDD 49 mm, 109% of predicted). Exercise echocardiogram was performed which was negative for ischaemia and Holter failed to demonstrate any arrhythmia. There was no other relevant family history and no evidence of a sudden death case in the families (both on the maternal or paternal side).
Questions:1. Do you consider a endocardial biopsy would have been of help in the diagnosis of this case to rule out storage disease?2. Do you agree with the medication and follow-ups plan?.3. Would you recommend ICD implantation on the basis of syncope and systolic impairment in a young patient? 4. What is your diagnosis in the index case?, and in the maternal grandmother?
This is the case of a young female patient presenting with syncopal episode and left ventricular systolic impairment (EF 40%) with non-dilated ventricle. ECG showed very low QRS and diffuse repolarization abnormalities (flat T- small negative T wave). No arrhythmias were demonstrated and was discharged on medication after a positive Tilt test. There was a family history of obstructive Hypertrophic Cardiomyopathy on the paternal side (uncle affected, father non-affected) and Dilated Cardiomyopathy on the maternal side (grandmother affected, mother non-affected).
The patient had a second syncopal episode that led to a new admission 2 months later. During her admission had a poorly tolerated episode of rapid ventricular tachycardia at a rate of 250 bpm (left bundle branch block morphology and inferior axis) requiring electrical cardioversion (figure 4). ICD was then implanted. ICD recordings showed a run of sustained ventricular tachycardia at rate of 155 bpm that required ATP therapy, and 5 NSVT episodes during the following 18 months after implantation. Amiodarone was added to bisoprolol and ramipril. The patient is currently asymptomatic with only very mild dyspnea on exercise.
Genetic testing of 5 desmosomal genes (PKP-2, DSP, DSG2, DSC2, PKG) related to Arrhythmogenic Cardiomyopathy and LMNA A/C was negative. Based on the phenotype and clinical presentation, study of the phospholamban gene (PLN) was also performed. A previously described mutation (R14del) in the PLN gene was identified. Mother, brother, 3 aunts and grandmother were carriers of the mutation.
Mutations in PLN and in particular R14del are related to a particular phenotype consistent with very low QRS voltage, ventricular arrhythmias and progression to heart failure requiring transplantation (1, 2). Phospolamban is a 52 aminacid key protein implicated in calcium handling within the cell. In a unphosphorilated form it is a inhibitor of the calcium uptaking bomb in the sarcoplasmic reticulum. But when it is phosphorilated by protein kinase A, this inhibition is relieved (3). Arg14del mutation results in a loss of an arginine residue at position 14 that is expected to disrupt the structure of the protein (4) as well as its unwinding upon phosphorilation (5).
R14del PLN mutation has been found in 15% of Dilated Cardiomyopathy (DCM) and 12% of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) cases in Holland (6). There was a clear founder effect of this mutation in the Dutch series. This is the first family reported of the same mutation in Spain. After the identification of the mutation in this family, we performed sequencing of the 2 DNA fragments of the PLN gene in 81 non-related consecutive patients diagnosed with DCM (55), ARVC (14) and HCM with low QRS voltage (12). None of these 81 patients had PLN mutations. In keeping with the Dutch cohort low voltage ECG was an early feature in carriers of R14del in our Spanish family. The penetrance of the disease was nevertheless incomplete. Screening of second degree relatives, despite unremarkable study of first degree relatives, led to identification of disease both in the parental and maternal side of the family. The role of a possible second mutation inherited from the paternal side on the early and severe presentation of the disease in the proband could not been ruled out (ongoing genetic study).
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