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Late-onset amyloidogenic transthyretin (ATTR) type familial amyloid polyneuropathy (FAP) shows features distinct from those of early-onset hereditary ATTR type FAP. We herein describe an asymptomatic 68-year-old man with late-onset ATTR type FAP whose serial annual electrocardiograms demonstrated progressive left bundle branch block. Latent but severe cardiac involvement seems to be one feature of late-onset ATTR type FAP, similar to senile systemic amyloidosis (SSA). Early differential diagnosis of late-onset ATTR type FAP from SSA is important because, currently, only the former has new therapeutic options available in Japan. The present case report, therefore, highlights the necessity of careful observation for periodic electrocardiograms.

Senile systemic amyloidosis is caused by a non-mutated form of transthyretin with the heart being the major organ involved. This infiltrative cardiomyopathy usually presents as slowly progressive heart failure. An 82-year-old female patient was admitted for newly diagnosed heart failure. A year later she presented with decompensated heart failure and syncope. Inpatient work-up showed persistently elevated troponin and N-terminal-pro BNP levels, rapid progression to severe left ventricular concentric hypertrophy, and sinus pauses on the Holter. Cardiac MRI revealed diffuse late gadolinium enhancement in the left ventricle. The demonstration of amyloid protein with the clinical findings and complementary investigations allowed for the diagnosis of senile systemic amyloidosis. LEARNING POINTS: Senile systemic amyloidosis is a rare disease with a common clinical presentation that is probably underdiagnosed in patients with heart failure with preserved systolic function.A new unexplained heart failure diagnosis, increased ventricular wall thickness and particularly low voltage on the ECG should raise the suspicion of cardiac amyloidosis.Histopathological evidence of amyloid deposition elsewhere and typical advanced imaging features can support the diagnosis, rendering endomyocardial biopsy no longer mandatory. info:eu-repo/semantics/publishedVersion

Cardiac amyloidosis (CA) is often misdiagnosed because of both physician-related and disease-related reasons including: fragmented knowledge among different specialties and subspecialties, shortage of centres and specialists dedicated to disease management, erroneous belief it is an incurable disease, rarity of the condition, intrinsic phenotypic heterogeneity, genotypic heterogeneity in transthyretin-related forms and the necessity of target organ tissue histological diagnosis in the vast majority of cases. Pitfalls, incorrect beliefs and deceits challenge not only the path to the diagnosis of CA but also the precise identification of aetiological subtype. The awareness of this condition is the most important prerequisite for the management of the risk of underdiagnoses and misdiagnosis. Almost all clinical, imaging and laboratory tests can be misinterpreted, but fortunately each of these diagnostic steps can also offer diagnostic “red flags” (i.e. highly suggestive findings that can foster the correct diagnostic suspicion and facilitate early, timely diagnosis). This is especially important because outcomes in CA are largely driven by the severity of cardiac dysfunction and emerging therapies are aimed at preventing further amyloid deposition.

[Aims]: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with multiple underlying causes.Wild-type transthyretin (TTR) amyloidosis (ATTRwt) is an underdiagnosed cause of HFpEF that might benefit from new specific treatments. ATTRwt can be diagnosed non-invasively by mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (mTc-DPD) scintigraphy. We sought to determine the prevalence of ATTRwt among elderly patients admitted due to HFpEF. [Methods and results]: We prospectively screened all consecutive patients .60 years old admitted due to HFpEF [left ventricular (LV) ejection fraction .50%] with LV hypertrophy (.12mm).All eligible patientswere offered a mTc-DPD scintigraphy. The study included 120 HFpEF patients (59% women, 82+8 years). A total of 16 patients (13.3%; 95% confidence interval: 7.2.19.5) showed a moderate-to-severe uptake on the mTc-DPD scintigraphy. All patients with a positive scan underwent genetic testing of the TTR gene, and no mutationswere found. An endomyocardial biopsywasperformed in four patients, confirmingATTRwt inall cases. There were no differences in age, gender, hypertension, diabetes, coronary artery disease, or atrial fibrillation between ATTRwt patients and patients with other HFpEF forms. Although patients with ATTRwt exhibited higher median N-terminal pro-brain natriuretic peptide (6467 vs. 3173 pg/L; P . 0.019), median troponin I (0.135 vs. 0.025 mg/L; P, 0.001), mean LV maximal wall thickness (17+3.4 vs. 14+2.5 mm; P . 0.001), rate of pericardial effusion (44 vs. 19%; P . 0.047), and rate of pacemakers (44 vs. 12%; P . 0.004), clinical overlap between ATTRwt and other HFpEF forms was high. [Conclusion]: ATTRwt is an underdiagnosed disease that accounts for a significant number (13%) of HFpEF cases. The effect of emerging TTR-modifying drugs should be evaluated in these patients., This work was partially supported by Pfizer Inc. through an Investigator Initiated Research Grant.

Amyloidosis is a disease characterized by depositions of amyloid in organs and tissues. It can be localized (in just one organ) or systemic. Cardiac amyloidosis is a debilitating disease and can lead to arrhythmias, deterioration of heart function and even sudden death. We reviewed PubMed/Medline, without time constraints, on the different nuclear imaging modalities that are used to visualize myocardial amyloid involvement. Several SPECT tracers have been used for this purpose. The results with these tracers in the evaluation of myocardial amyloidosis and their mechanisms of action are described. Most clinical evidence was found for the use of (123)I-MIBG. Myocardial defects in MIBG activity seem to correlate well with impaired cardiac sympathetic nerve endings due to amyloid deposits. (123)I-MIBG is an attractive option for objective evaluation of cardiac sympathetic level and may play an important role in the indirect measurement of the effect of amyloid myocardial infiltration. Other, less sensitive, options are (99m)Tc-aprotinin for imaging amyloid deposits and perhaps (99m)Tc-labelled phosphate derivatives, especially in the differential diagnosis of the aetiology of cardiac amyloidosis. PET tracers, despite the advantage of absolute quantification and higher resolution, are not yet well evaluated for the study of cardiac amyloidosis. Because of these advantages, there is still the need for further research in this field.

Mutant (MT) forms of transthyretin (TTR) cause the most common type of autosomal-dominant hereditary systemic amyloidosis—familial amyloidotic polyneuropathy (FAP). Until 20 years ago, FAP was thought to be an endemic disease, but FAP is known to occur worldwide. To date, more than 130 mutations in the TTR gene have been reported. Genotype-phenotype correlations are seen in FAP, and some variation in clinical presentation is often observed in individual kindreds with the same mutation and even among family members. Of the pathogenic TTR mutations, Val30Met was the first to be identified and is the most frequent known mutation found throughout the world. Studies of patients with FAP amyloidogenic TTR (ATTR) Val30Met documented sensorimotor polyneuropathy, autonomic dysfunction, heart and kidney failure, gastrointestinal tract (GI) disorders, and other symptoms leading to death, usually within 10 years of the onset of disease. Diagnosis is sometimes delayed, especially in patients without a clear family history and typical clinical manifestations, since diagnosis requires various studies and techniques such as histopathology, genetic testing, and mass spectrometry. For treatment of FAP, liver transplantation (LT) reportedly halts the progression of clinical manifestations. Exchange of an FAP patient’s diseased liver with a healthy liver causes MT TTR in the body to be replaced by wild-type (WT) TTR. Although clinical evaluations indicated that progression of other clinical symptoms such as peripheral neuropathy, GI symptoms, and renal involvement usually halted after LT in FAP ATTR Val30Met patients, recent studies suggested that LT failed to prevent progression of cardiac amyloidosis in FAP ATTR Val30Met patients after LT, with this failure reportedly being due to continued formation of amyloid that derived mainly from WT TTR secreted from the transplanted non-mutant liver graft. In recent years, many therapeutic strategies have been proposed, and several ongoing therapeutic trials involve, for example, stabilizers of TTR tetramers (tafamidis and diflunisal) and gene therapies to suppress TTR expression (antisense methods and use of small interfering RNAs). These novel therapies may prove to prevent progression of FAP.