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Esther González-López, Maria Gallego-Delgado, Gonzalo Guzzo-Merello, F. Javier de Haro-del Moral, Marta Cobo-Marcos, Carolina Robles, Belén Bornstein, Clara Salas, Enrique Lara-Pezzi, Luis Alonso-Pulpon, Pablo Garcia-Pavia, Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction, European Heart Journal, Volume 36, Issue 38, 7 October 2015, Pages 2585–2594, https://doi.org/10.1093/eurheartj/ehv338
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Abstract
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 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy. We sought to determine the prevalence of ATTRwt among elderly patients admitted due to HFpEF.
We prospectively screened all consecutive patients ≥60 years old admitted due to HFpEF [left ventricular (LV) ejection fraction ≥50%] with LV hypertrophy (≥12 mm). All eligible patients were offered a 99mTc-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 99mTc-DPD scintigraphy. All patients with a positive scan underwent genetic testing of the TTR gene, and no mutations were found. An endomyocardial biopsy was performed in four patients, confirming ATTRwt in all 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 µg/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.
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.
Comments
We welcome the interest of Dr Bonderman and Dr Mascherbauer in our work(1). As described in the article, the diagnosis of ATTRwt was based on a combination of cardiac involvement, absence of TTR mutations and an intense trazer uptake (grade 2-3) on 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy. Furthermore, 25% of these patients had histological proven cardiac TTR amyloidosis. As previously published, 99mTc-DPD scintigraphy has shown high especificity and sensitivity in differentiating TTR cardiac amyloidosis from AL(2).
Current gold standard for the diagnosis of cardiac amyloidosis lays on the demonstration of amyloid deposits from an endomyocardial biopsy coupled with immunohistochemistry or mass spectroscopy(3). As pointed out, CMR plays an important role as a non-invasive approach in the diagnosis of cardiac amyloidosis but it is not the gold standard for cardiac amyloid detection and it is not useful to determine the type of cardiac amyloid.
We agree that AL amyloidosis has been considered the most frequent form of cardiac amyloidosis so far(4,5). However, recent data poses the question whether ATTRwt could be more prevalent than previously considered as it has been largely underdiagnosed in the past(3,6).
The objetive of our work was to evaluate the presence of ATTRwt in patients with HFpEF. Prevalence of AL amyloidosis was therefore not investigated. The hypothesis of different underlying substrates in HFpEF has recently been raised as an explanation for the failure of clinical trials in this condition(7). As described by Dr Bonderman and Dr Mascherbauer, AL amyloidosis can nowadays be treated with immunotherapeutics but no specific therapies can be offered to ATTRwt patients yet. Therefore, we sought to investigate how many patients with HFpEF account for ATTRwt, highlighting the diversity of HFpEF and the need to look for specific entities and a tailored therapy according to the underlying disease.
In summary, estimation of the burden of all cardiac amyloid subtypes among HFpEF was not the aim of our study and we are not aware of any published data showing the prevalence of AL amyloidosis in HFpEF patients but Dr Bonderman and Dr Mascherbauer comment is very interesting and further investigation of the prevalence of AL cardiac amyloidosis among HFpEF patients would be highly desirable.
Esther Gonzalez-Lopez, MD, PhD
Pablo Garcia-Pavia, MD, PhD
Heart Failure and Inherited Cardiac Diseases Unit
Hospital Universitario Puerta de Hierro
Madrid, Spain
References
1. González-López E, Gallego-Delgado M, Guzzo-Merello G, de Haro-Del Moral FJ, Cobo-Marcos M, Robles C, Bornstein B, Salas C, Lara-Pezzi E, Alonso-Pulpon L, Garcia-Pavia P. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36:2585-94.
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