Presented by: Alexandros Protonotarios MD, Adalena Tsatsopoulou MD and Aris Anastasakis MD, PhD
A 43 year-old man presented due to his 14-year-old daughter’s sudden death. Post mortem diagnosis was myocarditis.
He was completely asymptomatic. Physical examination revealed mild palmoplantar keratosis without any other abnormal finding. His father had also died suddenly at the age of 50 years old but post mortem analysis had not been performed. (Fig 1).
His 12-lead resting ECG revealed repolarization abnormalities in lateral and inferior leads. Low voltage on limp and lateral precordial leads was notable, too. (Fig 2).
24–hour Holter monitoring revealed 1123 isolated monomorhic ventricular ectopics without any runs or episodes of sustained or non sustained ventricular arrhythmia. The SAECG was positive in all three parameters. (Fig 3).
Two-dimensional echocardiography was indicative only of a suspected mildly hypokinetic region on left ventricular apex ,EF:50%. No right ventricular abnormalities were observed.
Cardiac magnetic resonance revealed mild left ventricular dilatation with regional and apical dyskinetic areas EF:45-50%. Subepicardial late gadolinium enhancement on medial and apical regions of the left ventricle was obvious (Fig 4, arrows).
Although asymptomatic, on beta-blockers and ace inhibitor, waiting for hospital admission and further evaluation the father died suddenly during an emotional stress. Note that 1 week before his death his c/p exercise test was with in normal limits with no indications of ischemia or arrhythmias at peak exercise.
What is the most possible diagnosis?
How would you proceed to risk stratification?
Was he a high risk patient an why?
What the next step for management should be?
Would you procced to molecular genetic investigation?
Is there any indication of re-evaluating the family?
By Michael Arad MD, Heart Failure Institute, Leviev Heart Center, Sheba Hospital and Tel Aviv University, Israel
The patient was referred to hematologist. Bone marrow biopsy was negative for plasma cell dyscrasia but confirmed amyloid deposits around blood vessels. At this stage the niece of the patient brought a report from the National Amyloidosis Centre (UK) describing TTR cardiac amyloidosis and a S77Y TTR mutation in the late patient's sister. The same mutation was then confirmed in the patient. No other family members agreed to be genotyped or thoroughly evaluated. The patient is currently in NYHA IV, is treated in the heart failure daycare, has no neuropathy and refuses to try any experimental therapy.
Interestingly, we are familiar with another family of the exact same ethnic origin and the same mutation, who have an elderly onset familial polyneuropathy (TTR-FAP) but have no cardiomyopathy.
This case demonstrates the complexity of diagnosing AS/TTR amyloidosis in elderly patients with multiple comorbidities. In this case cardiac AS amyloidosis caused microvoltage, persistent troponin I elevation, decreased systolic and diastolic function and prominent tricuspid regurgitation but no ventricular hypertrophy. Once the diagnosis of amyloidosis is established, the type of amyloid needs to be defined by precise analytical methods such as mass spectroscopy. A strongly positive bone scan may probably be used as an alternative in appropriate cases. As demonstrated in our case, elderly age does not rule out a familial disease. Familial TTR amyloidosis classically presents either as polyneuropathy and/or as cardiomyopathy. TTR-FAP is a common presentation in Portuguese patients with V30M mutation while other Europeans with the same mutation present with maturity-onset cardiomyopathy. In our case the S77Y mutation caused a completely different phenotype in 2 families of the same ethnic origin.Accurate diagnosis of familial TTR amyloidosis is highly important not only for purpose of family planning but because novel therapies are already in use and are being developed to target this disease.
Adam Castaño, et al. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev. 2015 Mar;20(2):163-78. doi: 10.1007/s10741-014-9462-7.
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