Transthyretin amyloid cardiomyopathy (ATTR-CM) is the most common type of cardiac amyloidosis, and is significantly underdiagnosed.1 Disease management is focused on support therapy for heart failure (HF).

Although ATTR-CM usually presents as HF with preserved left ventricular ejection fraction (LVEF), nearly one third of patients have reduced LVEF at diagnosis.2 Optimal management of HF is challenging in this scenario and euvolemia becomes the cornerstone of HF management.

Despite their benefits in HF with reduced and mildly reduced LVEF,3 evidence supporting the use of angiotensin receptor-neprilysin inhibitors (ARNI) in ACTTR-CM is lacking. Moreover, they are usually described as poorly tolerated, mainly because of hypotension and renal impairment.1

We present our initial experience with patients with ACTTR-CM and HF with impaired LVEF who received ARNI. Our aim was to analyze the tolerance and safety of starting ARNI in this population.

We conducted a prospective observational study including consecutive patients referred to the Cardiomyopathy Unit between 2018 and 2021 with ACTTR-CM and impaired ejection fraction (LVEF <50%). ACTTR-CM was diagnosed using current recommendations.4 ARNI was started at a dose of 12/13 mg twice daily and titrated to maximum tolerated dose in all cases. Laboratory and clinical examinations were carried out before starting ARNI and at one, three and six months, as per the Unit's protocol. The study was approved by the local ethics committee and informed consent was obtained.

Six patients were included. All had been non-invasively diagnosed with wild-type ATTR-CM. The main characteristics of the study population are shown in Table 1. Patients were male (100%), aged 84.2±6.5 years, and had other comorbidities (five out of six had chronic kidney disease).

Clinical status at baseline suggested advanced HF. All patients had presented at least one decompensation in the last year. Functional class was usually poor (83.3% in New York Heart Association [NYHA] class III/IV). Mean baseline LVEF was 39.0±5.3% and severe diastolic dysfunction was present in all cases (E/e′ 20.0±3.3). Natriuretic peptides were highly elevated (mean N-terminal B-type natriuretic peptide [NT-proBNP] 7728.8±5458.1 pg/ml). As shown, patients were under medium to high doses of loop diuretics and most of them were receiving more than one diuretic.

ARNI was promptly started in most patients (4/6 within six months of ATTR-CM diagnosis). Maximum dose was not achieved in any case, but medium dose (49/51 mg twice daily) was tolerated in three out of six patients. Therapy onset was generally well tolerated. One patient (#1) needed a temporary withdrawal for one week due to symptoms of hypotension. Blood pressure measurements showed no clinically significant hypotension and renal function remained similar in all cases (estimated glomerular filtration rate improved in 50% of patients). Moderate hyperkalemia was observed in one case (#2) but was successfully controlled with dietary recommendations and medical therapy. No hospitalizations due to acute HF were observed within six months of starting ARNI.

The main result of our work was that, when carefully titrated, ARNI was well tolerated, with only mild deleterious effects on blood pressure or renal function. We also observed a general improvement in clinical status after ARNI onset as assessed by NYHA class, relief of edema, weight loss and decreased natriuretic peptides (Table 1).

Several factors could explain the results observed. Biologically, improvement in systolic and diastolic function with ARNI is based on its dual mechanism through angiotensin receptor and neprilysin inhibition. Both effects seem to be the main mechanisms leading to an increase in natriuresis and diuresis, vasodilation, reduction in sympathetic tone and antiremodeling effects.5 On the other hand, autonomic impairment is more important in light-chain and variant ATTR-CM, in which amyloid deposits occur in the nerves.6 In wild-type ATTR-CM, patients usually experience age-related autonomic dysfunction, which can be more easily managed.

In addition, ARNI have shown fewer side effects than angiotensin-converting enzyme inhibitors in outpatient management. This is especially important when dealing with aged patients.

It is noteworthy that one patient (#6) showed an improvement in LVEF, which is commonly assumed to be rare in patients with cardiac amyloidosis. However, several studies have described an improvement in LVEF after starting treatment with sacubitril-valsartan in patients with reduced LVEF.7 It is unknown if some of them may have had undiagnosed cardiac amyloidosis.

Finally, observational reports such as ours have major limitations that should be considered. More studies are needed to confirm our findings and support the use of ARNI in wild-type ATTR-CM with impaired ejection fraction.