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Past clinical history
At the age of 30 years, he was occasionally diagnosed with asymptomatic paroxysmal atrial fibrillation during a cardiological evaluation performed for sport suitability. In the following years, he suffered several paroxysmal atrial flutter and supraventricular tachycardia episodes. Routine cardiologic examination did not document cardiac disease.
At the age of 45 years, he complained a prolonged episode of chest pain; a non-Q myocardial infarction with angiographically normal coronary arteries was diagnosed.
One year later he underwent isthmo-inferior v.cava-tricuspid radiofrequency catheter ablation due to recurrent atrial fibrillation episodes. He was then given sotalol. The echocardiographic study showed mild left ventricular hypertrophy (12 mm), left ventricle end-diastolic diameter at upper limits, normal systolic function (LVEF 50%), mildly enlarged left atrium area, normal pulmonary pressures. During the following year, the patient showed recurrent supraventricular arrhythmias and heart failure symptoms; sotalol was discontinued and he was given amiodarone. Finally, he underwent ablation of the atrio-ventricular node with implantation of a biventricular pace-maker. He was then referred to our Centre for clinical and genetic evaluation.
Recent clinical history and clinical evaluation
At our first observation the patient showed mild effort dyspnea, peripheral edema. His ECG in sinus rhythm showed a normal PR interval and a wider QRS complex than those recorded in prior ECGs (Fig. 1a). The echocardiographic study showed impaired left ventricular ejection fraction (LVEF 35-40%), minimal enlargement of the left ventricle (end-diastolic diameter 58 mm). Wall thickness was still at upper limits only at the level of the interventricular septum (12 mm). Both atria were dilated; pulmonary pressures were increased, right ventricular function was slightly depressed and there was a mild pericardial effusion. In a few months, the symptoms worsened, as did LVEF (25%), pulmonary pressures and pericardial effusion. The right heart catheterisation showed a depressed cardiac index (1.42 and 1.16 l/min/m2 in two consecutive evaluations), high left ventricular filling pressures (PWP 25 mmHg) and atrial pressure (RAP 15 mmHg), depressed right ventricular systolic function. Nuclear magneticEndomyocardial biopsy excluded storage diseases and showed focal hypertrophy and irregular nuclei and interstitial fibrosis (fig. 1b). The serum creatine phosphokinase (sCPK) was mildly increased (378 U/l). The patient entered the waiting list for heart transplantation and underwent heart transplant 2 years later.
The genetic counselling was very difficult, as the patient had no contacts with his only sister. The family history was initially poorly contributory: the mother died of “cardiac disease” at the age of 50 years (fig. 1c). The patient had no information about the maternal relatives; clinical reports of the mother were not available.
Which diagnostic hypothesis could be done for this patient?
Which other investigations should be performed to facilitate the diagnosis?
The early clinical history raised the hypothesis of tachycardiomyopathy. The impaired left ventricular function, the enlarged left atrium in the presence of recurrent atrial arrhythmias supported the hypothesis of a hypokinetic and mildly dilated cardiomyopathy, also considering a potential contribution of the sotalol treatment. The presence of a mild pericardial effusion could be related to the recent device implantation. A contributory diagnostic marker in the proband was LV hypertrophy and severe evolution to end-stage heart failure over 5 years: progressive left ventricular dysfunction, biatrial enlargement, pulmonary hypertension in a mildly thickened ventricle. The histology confirmed hypertrophy of the myocytes and documented the interstitial fibrosis. The heart excised at transplantation showed wall thickness (fig. 2), 16 mm at the level of the interventricular septum and 15 mm at the level of lateral wall. A potential confounding marker was the mildly increased sCPK
Genetic counselling and family study
The genetic counselling was difficult, as the patient had no contacts with his only sister. The family history was initially poorly contributory: the mother died of “cardiac disease” at the age of 50 years. Clinical reports were not available. No information was available about the maternal relatives. We asked patient the permission of contacting the sister. She accepted to come to our centre and we discovered that she was affected by non-obstructive hypertrophic cardiomyopathy (HCM) that had a dilated and hypokinetic evolution. The clinical evaluation of her son documented an asymptomatic non-obstructive HCM (fig. 3).
Two genetic testing identified two mutations: p.M849C of the MYH7 gene and p.R597W of the MYBPC3 gene; the two mutations segregated with the phenotype in the family.
Final diagnosis: HCM with dilated congestive evolution associated with double MYH7+MYBPC3 mutations.
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