Neurohormonal Therapy in Patients With Transthyretin Cardiac Amyloidosis

Abstract

Background

Neurohormonal therapy is strongly recommended for heart failure with reduced left ventricular ejection fraction (LVEF). However, its role in transthyretin cardiac amyloidosis remains uncertain given concerns regarding tolerability and the perception that systolic dysfunction reflects an irreversible situation.

Cases Summary

We report 3 patients with wild-type transthyretin cardiac amyloidosis (wtATTR-CA) who initially presented with heart failure and reduced LVEF (≤35%). Guideline-directed medical therapy was initiated and was carefully titrated. During follow-up, these patients experienced clinical improvement and recovery of LVEF to ≥50%, allowing subsequent initiation of tafamidis, which is only approved for LVEF ≥50% in our country.

Discussion

These cases suggest that neurohormonal therapy may be feasible and beneficial in selected patients with wtATTR-CA and reduced LVEF, challenging the traditional paradigm of irreversible systolic dysfunction.

Take-Home Messages

Guideline-directed medical therapy may be considered on an individualized basis in patients with wtATTR-CA and reduced LVEF. Some patients may tolerate treatment and experience improvement.

Visual Summary

Neurohormonal therapy is well established and strongly recommended for the treatment of heart failure (HF) with reduced left ventricular ejection fraction (LVEF).¹ However, its role is less clear in patients with transthyretin cardiac amyloidosis (ATTR-CA).² HF is the most common clinical presentation in patients with ATTR-CA. A non-negligible proportion of patients with ATTR-CA present with reduced LVEF at diagnosis.³ Some series reflect up to 40% of the ATTR-CA population with LVEF <50%⁴ and approximately 22% with LVEF <40%.^3,5 This subgroup represents a challenging clinical scenario, as the role, tolerability, and potential benefit of guideline-directed medical therapy (GDMT) remain insufficiently defined in patients with ATTR-CA and reduced LVEF.

We present 3 different cases of patients with wild-type ATTR-CA (wtATTR-CA) who initially presented with reduced LVEF. In Spain, disease-modifying therapies are not reimbursed for patients with LVEF ≥50%, which considerably limits therapeutic options in this population. All transthoracic echocardiography (TTE) in this report were performed by expert cardiologists, and the LVEF data provided were calculated using the biplane Simpson's method if possible.

Clinical Presentation

Patient 1

A 75-year-old man presented to his referring hospital in 2023 with a transient ischemic attack of probable cardioembolic origin. Directed questioning revealed progressive deterioration in functional capacity over the previous months.

TTE showed an LVEF of 35% (Video 1), with no significant valvular disease but imaging findings suggestive of an infiltrative cardiomyopathy. The patient was referred to our center for further evaluation and follow-up.

Patient 2

A 66-year-old man was evaluated at his referring hospital in 2022 for worsening functional class and signs of congestion. Relevant medical history included lumbar spinal stenosis, bilateral carpal tunnel syndrome requiring surgery, and untreated Peyronie disease.

TTE showed an LVEF of 35% (Videos 2 and 3), an interventricular septum thickness of 23 mm, mild pericardial effusion, and aortic valve sclerosis. The patient was also diagnosed with atrial fibrillation, and a rhythm-control strategy with amiodarone was initiated. Cardiac magnetic resonance showed an LVEF of 35% and suspicion of infiltrative cardiopathy.

The patient was admitted again in 2024 with advanced HF and was referred to our center for evaluation for advanced HF therapies.

Patient 3

An 87-year-old woman with hypertension, dyslipidemia, and obesity was evaluated by the internal medicine department in 2023 for palpitations and exertional dyspnea. She was diagnosed with atrial fibrillation and decompensated HF.

TTE demonstrated an LVEF of 34% (Videos 4 and 5), moderate right ventricular dysfunction, severe myocardial wall thickening, and aortic valve sclerosis. She was referred to the HF unit with suspected infiltrative cardiomyopathy.

Diagnostic Work-Up

Patient 1

Given the suspicion of infiltrative disease, a bone scintigraphy and hematologic evaluation were performed. Bone scintigraphy with technetium-99m-DPD (3,3-diphosphono-1,2-propanodicarboxylic acid) was performed, showing a grade 3 myocardial uptake.

Laboratory evaluation revealed an abnormal serum-free light-chain kappa/lambda ratio (1.83) with normal renal function (estimated glomerular filtration rate: 75 mL/min/1.73 m²), prompting an endomyocardial biopsy. Histology demonstrated amyloid deposition. Immunohistochemistry was positive for transthyretin, and mass spectrometry confirmed transthyretin amyloidosis. Genetic testing for pathogenic variants in the TTR gene was negative, so diagnosis of wtATTR-CA was established. Coronary computed tomography ruled out obstructive coronary disease. Monitorization showed good rate control.

Patient 2

Based on the clinical history and imaging findings, comprehensive laboratory testing was performed and showed no hematologic abnormalities. DPD scintigraphy demonstrated grade 3 myocardial uptake. Sequencing of the TTR gene demonstrated no pathogenic variants, allowing the final diagnosis of wtATTR-CA. Initial laboratory evaluation showed an N-terminal pro–B-type natriuretic peptide (NT-proBNP) level of 8,245 pg/mL (laboratory range: 0-150 pg/mL), with preserved renal function.

Patient 3

TTE findings were suggestive of an infiltrative cardiomyopathy. Laboratory testing showed no hematologic abnormalities. Therefore, DPD scintigraphy was performed and demonstrated grade 2 myocardial uptake. Finally, a normal TTR genetic test led to the diagnosis of wtATTR-CA.

Interventions

Patient 1

After the diagnosis of HF with reduced ejection fraction (HFrEF) secondary to wtATTR-CA, dapagliflozin 10 mg daily and low-dose beta-blocker therapy were initiated. Also, the angiotensin receptor blocker was replaced with sacubitril-valsartan (SV).

During follow-up visits every few weeks, eplerenone 25 mg was introduced and was subsequently up-titrated to 50 mg daily. SV was progressively up-titrated to 97/103 mg twice daily, allowing a reduction in loop diuretic therapy to 20 mg of furosemide. Bisoprolol could not be titrated further because of resting heart rates of approximately 60 beats/min with 2.5 mg.

Patient 2

Given the underlying cardiomyopathy, absence of specific therapy, and recurrent HF decompensations in a relatively young patient, he was referred for evaluation for advanced HF therapies.

During hospitalization, treatment with dapagliflozin 10 mg, eplerenone 25 mg, and SV 24/26 mg twice daily was initiated. Bisoprolol was titrated to 2.5 mg daily and eplerenone to 50 mg daily. The patient experienced occasional orthostatic symptoms, which resolved after discontinuation of loop diuretics.

Patient 3

After the diagnosis of HF with reduced LVEF, treatment was initiated with furosemide 60 mg, empagliflozin 10 mg, eplerenone 25 mg, bisoprolol 5 mg, and ramipril 2.5 mg (all daily). Bisoprolol was titrated to 10 mg because of atrial fibrillation with rapid ventricular response.

After the diagnosis of ATTR-CA, neurohormonal therapy was optimized. Ramipril was replaced with SV 24/26 mg twice daily, which was progressively titrated to 97/103 mg twice daily. Eplerenone was increased to 50 mg but was later reduced to 25 mg daily because of hyperkalemia and renal dysfunction.

Outcomes

Patient 1

After optimization of therapy at tolerated doses and resolution of congestion, repeat TTE performed in March 2024 showed improvement in LVEF to 51% (Video 6).

After this finding, tafamidis therapy was initiated and has been maintained since then. The patient has had no HF decompensations during follow up (last visit in May 2026). The baseline NT-proBNP level was 4,333 pg/mL and decreased to 522 pg/mL after optimization of neurohormonal therapy. Renal function and potassium levels remained within normal ranges and persists at NYHA functional class II.

Patient 2

The patient remained in sinus rhythm, with heart rates between 50 and 70 beats/min. NT-proBNP after treatment optimization was 1,789 pg/mL. An early first follow-up visit was performed after discharge. After 3 months, SV was able to be titrated to 49/51 mg twice daily with good tolerance, and renal function remained preserved. After optimization of therapy to tolerated doses, repeat TTE demonstrated an LVEF of 50% (Videos 7 and 8), accompanied by clinical improvement. The patient was referred to his original center, where tafamidis therapy was initiated.

Currently, he has had no HF hospitalizations (last visit in June 2026) and maintains normal renal function. Cardiopulmonary exercise testing showed a peak oxygen consumption rate of 20.4 mL/kg/min. Repeat TTE showed a maintained LVEF of 50%.

Patient 3

During follow-up, the patient tolerated SV 97/103 mg twice daily, eplerenone 25 mg, bisoprolol 10 mg, and empagliflozin 10 mg daily. She experienced 1 episode of HF decompensation related to a respiratory infection in January 2025, which was managed on an outpatient basis. Follow-up TTE performed in April 2025 showed improvement in LVEF to 55% (Videos 9 and 10). Tafamidis therapy was subsequently initiated and was well tolerated.

At follow-up in December 2025, NT-proBNP had decreased to 3,124 pg/mL from a baseline NT-proBNP of 10,111 pg/mL. Renal function remained stable, with an estimated glomerular filtration rate of approximately 40 mL/min/1.73 m².

Currently, the patient remains at NYHA functional class II, with good tolerance to neurohormonal therapy. Regular visits are performed every 3 months.

Discussion

ATTR-CA represents a complex therapeutic challenge, particularly in patients presenting with HFrEF. Traditionally, clinical guidelines have cautioned against the routine use of GDMT in this population because of the unique pathophysiological features of the disease.² However, given that >20% of patients with ATTR-CA present with an LVEF of <40%,⁵ it is essential to clarify the role, tolerability, and potential benefit of GDMT in this population. The 3 cases presented here (summarized in Table 1) illustrate a clinically relevant scenario: patients with wtATTR-CA and reduced LVEF who experienced recovery of ventricular function after HF therapy optimization. This is a relevant situation in our country, subsequently allowing initiation of tafamidis as disease-modifying therapy, which is approved only with LVEF ≥50%.

Table 1.

Treatment Modification From the Beginning of Follow-Up Until the Last Clinic Visit

	First Visit	Interim Visit	Last Visit
Patient 1
Treatment	Olmesartan: 10 mg Furosemide: 40 mg	SV: 24/26 mg twice daily Bisoprolol: 2.5 mg Eplerenone: 25 mg Dapagliflozin: 10 mg	SV: 97/103 mg twice daily Bisoprolol: 2.5 mg Eplerenone: 50 mg Dapagliflozin: 10 mg Tafamidis: 61 mg
Vital signs	BP: 142/73 mm Hg HR: 64 beats/min	BP: 138/76 mm Hg HR: 67 beats/min	BP: 129/68 mm Hg HR: 62 beats/min
NT-proBNP (pg/mL)	4,333	1,496	522
Ejection fraction (%)	35	—	51
UK NAC stage	II	I	I
Patient 2
Treatment	Bisoprolol: 1.25 mg Spironolactone: 25 mg Dapagliflozin: 10 mg Furosemide: 40 mg	Bisoprolol: 2.5 mg Eplerenone: 50 mg Dapagliflozin: 10 mg SV: 24/26 mg twice daily	Bisoprolol: 2.5 mg Eplerenone: 50 mg SV: 49/51 mg twice daily Dapagliflozin: 10 mg Tafamidis: 61 mg
Vital signs	BP: 106/59 mm Hg HR: 50 beats/min	BP: 94/58 mm Hg HR: 62 beats/min	BP: 110/70 mm Hg HR: 50 beats/min
NT-proBNP (pg/mL)	8,245	2,231	1789
Ejection fraction (%)	35	—	50
UK NAC stage	II	I	I
Patient 3
Treatment	Bisoprolol: 5 mg Ramipril: 2.5 mg Furosemide: 40 mg	SV: 24/26 mg twice daily Bisoprolol: 7.5 mg Eplerenone: 25 mg Empagliflozin: 10 mg Furosemide: 60 mg	Bisoprolol: 10 mg SV: 97/103 mg twice daily Eplerenone: 25 mg Empagliflozin: 10 mg Furosemide: 40 mg Tafamidis: 61 mg
Vital signs	BP: 109/87 mm Hg HR: 84 beats/min	BP: 114/74 mm Hg HR: 81 beats/min	BP: 128/76 mm Hg HR: 73 beats/min
NT-proBNP (pg/mL)	10,111	6,459	3,124
Ejection fraction (%)	34	38	55
UK NAC stage	III	III	II

All treatments frequencies were daily with the exception of SV, which was twice daily.

BP = blood pressure; HR = heart rate; NT-proBNP = N-terminal pro–B-type natriuretic peptide; SV = sacubitril-valsartan; UK NAC = United Kingdom National Amyloidosis Center.

GDMT for HFrEF has historically been considered poorly tolerated and of uncertain benefit in cardiac amyloidosis. This perception is partly explained by the restrictive physiology of the disease, in which increased ventricular stiffness and impaired diastolic filling result in a relatively fixed stroke volume, making cardiac output highly dependent on heart rate and preload. As a result, therapies that reduce heart rate or blood pressure may precipitate hypotension, bradycardia, worsening congestion, or renal dysfunction, particularly in patients with autonomic dysfunction, chronotropic insufficiency, conduction disease, or renal impairment. However, these concerns have often been extrapolated across the cardiac amyloidosis spectrum, despite relevant differences between amyloid light-chain amyloidosis, hereditary transthyretin amyloidosis, and wtATTR-CA. Compared with amyloid light-chain amyloidosis, which may be characterized by direct light-chain cardiotoxicity, rapid progression, and systemic involvement, and hereditary transthyretin amyloidosis, in which autonomic neuropathy is more frequent, wtATTR-CA usually presents as a predominantly cardiac phenotype with less frequent autonomic involvement. This may partly explain why carefully selected patients with wtATTR-CA, reduced LVEF, preserved blood pressure, and no major autonomic symptoms may tolerate individualized GDMT.^2,5

Recent observational evidence suggests that beta-blockers,^5,6 mineralocorticoid receptor antagonists,⁵ and sodium-glucose cotransporter 2 inhibitors⁷ are generally well tolerated and potentially effective, particularly in patients with wtATTR-CA, a population in which autonomic nervous system involvement is less prevalent than in those with the hereditary form of the disease.⁸ Therefore, it appears reasonable that selected patients with cardiac amyloidosis and reduced LVEF may derive benefit from the careful implementation of these therapies.^5,9,10 It is also reported that patients with wtATTR-CA may have a similar and even possibly greater neurohormonal activation than patients with HF of other etiologies. Consequently, neurohormonal modulation might provide prognostic benefits for patients with wtATTR-CA.¹⁰

In the cases presented here, individualized HF treatment challenges the traditional paradigm that ventricular dysfunction in cardiac amyloidosis is uniformly progressive and unresponsive to conventional HF therapies. Although the predominant pathophysiology involves extracellular amyloid deposition and increased myocardial stiffness, several additional mechanisms may contribute to systolic dysfunction, including microvascular dysfunction, inflammation, and neurohormonal activation. Neurohormonal activation may partly reflect the chronic hemodynamic burden imposed by amyloid infiltration, with elevated filling pressures, reduced stroke volume, and congestion.⁵ These mechanisms may be partially reversible or modifiable, providing a plausible explanation for the observed improvement in LVEF.^5,11 Importantly, it is necessary to rule out other causes of HFrEF, such as ischemic cardiomyopathy, arrhythmias, or other coexisting conditions. In the cases presented, additional tests were performed to investigate other causes of reduced LVEF.

As mentioned above, recent observational studies have begun to explore the role of GDMT in cardiac amyloidosis. Data from retrospective cohorts suggest that mineralocorticoid receptor antagonists may be associated with improved outcomes and are generally well tolerated,⁵ whereas low-dose beta-blockers may be beneficial specifically in patients with reduced LVEF.^5,6 Although there is currently no evidence supporting the use of SV in this population, there is likewise no evidence demonstrating that it is poorly tolerated or harmful in patients with ATTR-CA. If we extrapolate from the experience with beta-blockers, a therapy that was historically considered poorly tolerated for this condition but has subsequently shown acceptable tolerability in selected patients, it appears reasonable to consider cautious initiation of SV in carefully selected individuals. Importantly, most available studies have focused on mortality and hospitalization outcomes rather than ventricular remodeling or recovery of systolic function, and reports describing improvement in LVEF remain scarce.^9,10,12

The cases described here are clinically relevant because they illustrate a rarely documented phenomenon: recovery of LVEF after HF therapy in patients with wtATTR-CA, enabling subsequent initiation of tafamidis. This strategy may have important implications for clinical practice, particularly in health care settings such as ours, where disease-specific therapies are only reimbursed when LVEF exceeds 50%; but it is also relevant in other settings were modifying disease treatments can be administered, regardless of LVEF, given that GDMT could be associated with a prognostic benefit in wtATTR-CA. Until further data become available, individualized treatment strategies and cautious implementation of HF therapies may represent a reasonable approach in selected patients with wtATTR-CA and reduced LVEF.

This report has several limitations, as it is a retrospective case series and includes only selected patients who tolerated GDMT and experienced improvement in LVEF. Therefore, its findings should be interpreted with caution, and further evidence is needed before making generalized recommendations regarding GDMT. Importantly, because this study does not provide a denominator of all patients with ATTR-CA and reduced LVEF managed at our institution, we cannot estimate the likelihood of GDMT tolerability, treatment success, or LVEF recovery in this population, nor can we compare these cases with patients who did not tolerate GDMT or did not experience similar improvement. Thus, our findings should not be interpreted as supporting systematic GDMT optimization in all patients with ATTR-CA. More recent studies suggest that these treatments may provide benefit, and additional studies are currently ongoing. The retrospective design may have led to the loss of relevant information regarding other potential causes of ventricular dysfunction, although the electronic medical record system includes all patient medical records across the region. Echocardiograms were not scheduled according to a uniform protocol in all patients; however, they were performed based on clinical indication and by experienced echocardiographers.¹²

Conclusions

Neurohormonal therapy in patients with HFrEF secondary to wtATTR-CA may be considered in selected patients, taking into account potential intolerance but with a possible benefit of LVEF recovery similar to that observed in patients with other cardiomyopathies. Further dedicated studies are needed to generate robust evidence in this field.

Visual Summary.

HFrEF and Wild-Type Transthyretin Cardiac Cardiac Amyloidosis

♂ = male; ♀ = female; EF = ejection fraction; GDMT = guideline-directed medical therapy; LVEF = left ventricular ejection fraction; HFrEF = heart failure with reduced ejection fraction; SV = sacubitril-valsartan; yo = years old.

Funding Support and Author Disclosures

Dr Enríquez-Vázquez has received funding from the Instituto de Salud Carlos III, Madrid, Spain (ISCIII) through contract éJR24/00059, cofunded by the European Union. Dr Padilla-Bautista has received funding from ISCIII through contract CM25/00135. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Take-Home Messages

• •It is not unusual that patients with wtATTR-CA may present with reduced left ventricular ejection fraction.
• •Neurohormonal therapy could be an option in patients with wtATTR-CA and ventricular dysfunction, in combination with disease-modifying therapy, although further studies are needed in this regard.

Appendix

Video 1

Apical 4-Chamber View of Patient 1 at Diagnosis

Video 2

Apical 4-Chamber View of Patient 2 at Diagnosis

Video 3

Apical 2-Chamber View of Patient 2 at Diagnosis

Video 4

Apical 4-Chamber View of Patient 3 at Diagnosis

Video 5

Apical 2-Chamber View of Patient 3 at Diagnosis

Video 6

Apical 3-Chamber View of Patient 1 at Follow-Up

Video 7

Apical 4-Chamber View of Patient 2 at Follow-Up

Video 8

Apical 2-Chamber View of Patient 2 at Follow-Up

Video 9

Apical 4-Chamber View of Patient 3 at Follow-Up

Video 10

Apical 2-Chamber View of Patient 3 at Follow-Up