Is cardiac amyloidosis hiding behind it?

In those over 65, heart failure is the most common reason for hospitalization. Clarification of the cause of the disease is essential to direct patients to targeted therapy. Patients with cardiac ATTR amyloidosis are an important HFpEF subgroup for whom there is a specific therapeutic option that has been shown to improve prognosis.

If heart failure (HF) is suspected, the NT-proBNP parameter should be obtained and/or transthoracic echocardiography should be performed. The latter is the central imaging modality in the diagnosis of HF. In patients with typical symptoms and elevated NTproBNP levels (≥125 pg/ml), the presence of heart failure is likely [1]. Echocardiography may already provide initial clues to possible causes of heart failure (e.g., wall motion abnormalities, valvular vitiation, infiltrative processes, cardiomyopathies, diastolic dysfunction) [1]. More advanced methods to determine the cause of HF include cardiac MRI (ischemic cardiomyopathy, amyloidosis, myocarditis) or scintigraphy (coronary artery disease, ATTRwt amyloidosis) [2].

Classical classification of heart failure is based on left ventricular ejection fraction findings into HFrEF (HF with reduced ejection fraction, <40%); HFmrEF (HF with moderately reduced ejection fraction, 40-49%); and HFpEF (HF with preserved ejection fraction, ≥50%).

HFpEF diagnostic criteria according to current ESC guideline

According to the ESC guideline on the management of heart failure, updated in 2021, the three essential criteria for HFpEF [3] are:

Symptoms and signs of heart failure
LVEF ≥50%
Objective evidence of structural and/or functional cardiac abnormalities consistent with left ventricular diastolic dysfunction and elevated LV filling pressures, including elevated natriuetic peptides.

Patients with HFpEF are on average older and more often female compared with HFrEF and HFmrEF sufferers. In addition, HFpEF is associated with atrial fibrillation, chronic kidney disease (CKD), and other noncardiovascular comorbidities [4]. Clarification of the underlying etiology is very important in HFpEF in order to initiate targeted pharmacological treatment (Fig. 1) .

Identify and treat patients with ATTR-CM

In a prospective study of 120 subjects, 13% of patients over 60 years of age who were hospitalized for heart failure with preserved ejection fraction (HFpEF) were found to have ATTR amyloidosis (wtATTR-KM) as an underlying disease [5]. Cardiac transthyretin amyloidosis (ATTR-CM) involves the deposition of misfolded transthyretin. A distinction is made between the sporadic wild-type variant (wtATTR) and the hereditary mutant form (mATTR). ATTR-CM can be screened by imaging (cardiac MRI or scintigraphic techniques) and immunofixation with determination of free light chains; biopsy and/or genetic testing is required for definitive diagnosis [6]. Whereas the administration of classic heart failure drug therapies such as ACE inhibitors, angiotensin-1 receptor antagonists, and beta-blockers showed a clear survival benefit in patients with HFrEF, this was not the case in HFpEF sufferers [7–9]. Because of risks of side effects, caution should be exercised in the use of beta-blockers, renin-angiotensin-aldosterone inhibitors, and diuretics in patients with ATTR-CM [6].

Forms of Amyloidosis with Cardiac Manifestation
In amyloidoses, proteins deposit as insoluble fibrillar aggregates as a result of a conformational change. Systemic forms of amyloidosis affecting the heart include, in particular, light chain (AL) and ATTR amyloidoses. The latter results in the deposition of misfolded transthyretin. A distinction is made between the wild-type (wtATTR) form and the mutant form (mATTR). In addition to specific cardiac biomarkers, modern noninvasive imaging techniques such as cardiac MRI or scintigraphic techniques are available nowadays, which can be used in addition to conventional echocardiography to diagnose cardiac amyloidosis and assess its severity.

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Tafamidis (^Vindaquel®) is a specific therapeutic option for the treatment of heart failure in ATTR patients. Studies showed that this tetramer stabilizer can slow the progression of cardiomyopathy and reduce the risk of hospitalization [10,11]. Tafamidis selectively binds with high affinity to transthyretin, slowing the dissociation of TTR tetramers into TTR monomers and thereby reducing further aggregation of amyloid fibrils [10]. In the ATTR-ACT trial, the tafamidis arm reduced all-cause mortality and cardiovascular-related rehospitalizations in patients with wtATTR and mATTR [10].

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ESC Pocket Guideline: Acute and Chronic Heart Failure, German Society of Cardiology (DGK) 2021, https://leitlinien.dgk.org, (last accessed 27.06.2023).
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