European Heart Journal (2024) 00, 1–15 STATE OF THE ART REVIEW

https://doi.org/10.1093/eurheartj/ehae811 Heart failure and cardiomyopathies

Transthyretin amyloid cardiomyopathy: a

paradigm for advancing precision medicine

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1,2 3 1,2,4,5,
Esther Gonzalez-Lopez , Mathew S. Maurer , and Pablo Garcia-Pavia *
1
Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, IDIPHISA, Manuel de Falla, 1, 28222 Majadahonda, Madrid, Spain; 2CIBER Cardiovascular, Instituto de
Salud Carlos III, Avenida Monforte de Lemos 3-5. Pabellón 11. Planta 0. 28029 Madrid, Spain; 3Division of Cardiology, Department of Medicine, Columbia University Irving Medical Centre,
New York, NY, USA; 4Universidad Francisco de Vitoria, M-515; Km 1, 800, 282223 Pozuelo de Alarcón, Madrid, Spain; and 5Miocardiopatías Hereditarias, Centro Nacional de
Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain

Received 25 May 2024; revised 25 July 2024; accepted 8 November 2024

Graphical Abstract

Transthyretin cardiac amyloidosis as an example of precision medicine in cardiology

New specific therapies acting

Elucidation of underlying
at different steps of the TTR Pending questions
disease mechanisms
amyloidogenic cascade

Initial therapy according

Suppressors to patient’s profile
Gene editing (NTLA-2001)
Gene silencers: Assessing response to therapy
Advances in imaging techniques: Patisiran
Non-invasive diagnosis possible Inotersen
Vutrisiran
Switching from one agent to another
Eplontersen

Stabilizers
Tafamidis Deprescribing treatment
Diflunisal
Precise data of the epidemiology:
Acoramidis
High prevalence of the disease Long-term safety of TTR depletion
in common clinical scenarios Removers
Heart failure ALX2220/NI006
Treatment of pre-symptomatic
Aortic stenosis Coramitug patients and ATTRv gene carriers
LVH/HCM AT-02

Transthyretin cardiac amyloidosis (ATTR-CM) as a paradigm for advancing precision medicine: factors that have fostered the development of new specific
therapies in ATTR-CM, available agents, and drugs under development along with unresolved questions in the therapeutic management of these patients.

* Corresponding author. Email: pablogpavia@yahoo.es

© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.
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2 Gonzalez-Lopez et al.

Abstract

Development of specific therapies addressing the underlying diseases’ mechanisms constitutes the basis of precision medicine. Transthyretin cardiac
amyloidosis (ATTR-CM) is an exemplar of precise therapeutic approach in the field of heart failure and cardiomyopathies. A better understanding of
the underlying pathophysiology, more precise data of its epidemiology, and advances in imaging techniques that allow non-invasive diagnosis have
fostered the development of new and very effective specific therapies for ATTR-CM. Therapeutic advances have revolutionized the field, transform­
ing a rare, devastating, and untreatable disease into a more common disease with several therapeutic alternatives available. Three main types of

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therapies (stabilizers, suppressors, and degraders) that act at different points of the amyloidogenic cascade have been developed or are currently
under investigation. In this review, the key advances in pathophysiology and epidemiology that have occurred in the last decades along with the
different therapeutic alternatives available or under development for ATTR-CM are described, illustrating the role of precision medicine applied
to cardiovascular disorders. Pending questions that would need to be answered in upcoming years are also reviewed.
.............................................................................................................................................................................................
Keywords Amyloid • Cardiac amyloidosis • Transthyretin • Heart failure

Introduction the liver, which transports vitamin A–retinol-binding protein and

thyroxin.13 Instability of the TTR molecule and proteolytic cleavage
Development of specific therapies addressing the underlying diseases’ leads to dissociation of the tetramer into dimers and monomers and
mechanisms constitutes the basis of precision medicine. Those thera­ subsequent monomer misfolding produce soluble misfolded aggregates
peutic advances are possible due to a better characterization of dis­ and insoluble aggregates.13 Insoluble aggregates ultimately generate
eases, a better understanding of their natural history, and underlying amyloid fibrils and promote deposition of additional misfolded mono­
pathophysiology along with advances in imaging techniques and break­ mers fostering growth of amyloid fibrils.14
throughs in gene sequencing techniques. Although other medical spe­ Transthyretin amyloidosis is a systemic disease, but cardiac
cialties like oncology or haematology have embraced this precision involvement is responsible for most of the mortality and morbidity.
medicine approach years ago, only recently has the cardiovascular Transthyretin deposition results in cardiac dysfunction and HF, recur­
community witnessed how a personalized approach is becoming rent hospitalizations, and ultimately death.15,16 Given its progressive na­
part of mainstream cardiology.1 The field of heart failure (HF) and car­ ture, ATTR-CM is characterized by worsening in quality of life and
diomyopathies particularly exemplify the paradigm shift that will trans­ disability. Life expectancy was only of 2.5–3.5 years,17,18 but has im­
form how we approach patients (and their families) in the next proved lately due to an earlier diagnosis, better management, and spe­
decades.2 cific therapies.
Transthyretin cardiac amyloidosis (ATTR-CM), once considered a Several studies conducted in the last decade have demonstrated the
rare cause of restrictive cardiomyopathy, is an exemplar of this new important contribution of ATTR-CM to common cardiovascular clinic­
paradigm where tailored therapies are progressively replacing the al scenarios such as HF with preserved ejection fraction (HFpEF), se­
‘one-fits-all’ model that has predominated clinical practice over the vere aortic stenosis in the elderly, or increased left ventricular (LV)
last 30 years. A better understanding of the underlying pathophysiology wall thickness.19–22 A recent meta-analysis grouped the screening stud­
of transthyretin (TTR) amyloid formation,3 advances in imaging ies performed up to January 2022 and found that ATTR-CM was pre­
techniques that facilitated a more precise epidemiology of the sent in 12% of patients with HFpEF, 10–15% of elderly patients with
disease,4–6 and the key driver of new specific and highly effective severe aortic stenosis undergoing valve replacement, and 7% of patients
therapies7–10 have revolutionized the field transforming what it used with LV wall thickness ≥15 mm.3 Screening studies in other less ex­
to be a rare disease with a devastating prognosis into a more common plored scenarios like HF with reduced ejection fraction or cardiac con­
disease with several therapeutic alternatives (Figure 1). In this review, duction disorders23,24 have also shown that ATTR-CM is not
we describe the key advances in pathophysiology and epidemiology uncommon and is certainly far from being a rare disease for the prac­
that have occurred in the last decades along with the different thera­ tising cardiologist (Figure 3).
peutic alternatives available or under development for ATTR-CM to il­
lustrate the role of precision medicine applied to cardiovascular
disorders. Disease-modifying therapies
Therapeutic advances in light chain amyloidosis (AL) and secondary
amyloidosis over the last 20 years have shown that reducing the circu­
Pathophysiology and epidemiology lating concentration of the amyloid precursor proteins dramatically im­
Transthyretin cardiac amyloidosis is a progressive disease caused by proves the prognosis of systemic amyloidosis.25,26
the extracellular deposition of TTR in the heart. Gene variants result­ Transthyretin cardiac amyloidosis therapeutic approaches have his­
ing in TTR instability cause hereditary ATTR (ATTRv), whereas an torically followed the same premise of reducing the precursor protein.
age-related failure of homoeostatic mechanisms among other un­ Until recently, the only therapy available (and only for some ATTRv pa­
known factors is responsible for the wild-type form of the disease tients) was liver transplantation. Liver transplantation allowed replace­
(ATTRwt). ment of variant TTR by wild-type TTR but was associated with several
The formation process of amyloid fibrils (amyloidogenic cascade) is limitations including donor shortage, surgical risks, complications de­
currently considered to be similar for both ATTRv and ATTRwt11,12 rived from immunosuppression, and subsequent amyloid progression
(Figure 2). Transthyretin is a tetrameric protein mainly produced by due to accumulation of wild-type TTR in the pre-existing ATTRv
Transthyretin amyloid cardiomyopathy 3

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Figure 1 Advances in knowledge in transthyretin cardiac amyloidosis

Figure 2 Transthyretin amyloidogenic cascade

deposits.27 To overcome these limitations and based on a better under­ Tafamidis

standing of the pathophysiology, new therapies acting at different Tafamidis stabilizes TTR by binding to the T4-binding site. Following
points of the TTR amyloidogenic cascade have been developed or the approval of tafamidis 20 mg for ATTRv with polyneuropathy,
are currently under investigation. ATTR-ACT was the first trial assessing a specific therapy for ATTR-CM.
Suppressors were designed to knockdown TTR production at the ATTR-ACT enrolled 441 patients, randomized to 80 mg of tafamidis me­
liver. Reduction of TTR production decreases circulating TTR limiting glumine, 20 mg of tafamidis meglumine, or placebo in a 2:1:2 fashion and
fibril formation. Stabilizers act by binding to the circulating TTR tetra­ followed over 30 months. Histological diagnosis was required as well as
mers limiting their fragmentation and the formation of amyloid fibrils’ a previous history of HF and a NTproBNP ≥600 pg/mL (Table 1).7
precursors. Lastly, degraders are therapies designed to promote The trial showed a 30% relative reduction in mortality, with a num­
removal of amyloid fibrils (Figure 4). While degraders are under ber needed to treat (NNT) of 7.5 to prevent one death and a 32% rela­
investigation in clinical trials, both reducers and stabilizers have already tive reduction in the rate of cardiovascular (CV) hospitalization and a
demonstrated efficacy in ATTR. NNT of 4 to prevent one CV hospitalization per year.
Tafamidis-treated patients exhibited a significant reduction in the de­
cline in the distance at the 6-min walk test (6MWT) and in quality of life
Transthyretin stabilizers assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ).7
Transthyretin stabilizers prevent tetramer degradation into dimers and Differences in survival emerged after 18 months of treatment, al­
monomers. Three stabilizers have been studied in ATTR-CM: tafamidis, though improvements in 6MWT and KCCQ were evident at 6 months.
diflunisal, and acoramidis. Patients who were in NYHA III class showed an increase in the rate of
4 Gonzalez-Lopez et al.

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Figure 3 Epidemiology of transthyretin cardiac amyloidosis

Figure 4 Transthyretin amyloidosis-specific therapies

CV hospitalizations, and the reduction in mortality in them was lower ATTR-ACT was not designed to test dosage efficacy, and the pri­
(16.3%) compared with individuals in NYHAs I and II (64.5% and 39.6%, mary endpoint was a pooled analysis of 80 and 20 mg, but subsequent
respectively) leading to limitations of reimbursement in certain coun­ analysis including the long-term extension (LTE) study showed that re­
tries for patients at NYHA III and reinforcing the need of early diagnosis duction in all-cause mortality was greater with 80 mg than with 20 mg,
and prompt initiation of treatment. without dose-related side effects.28 Latter development of tafamidis
Transthyretin amyloid cardiomyopathy 5

61 mg free acid, bioequivalent to tafamidis meglumine 80 mg, simplified Acoramidis

the number of pills to be taken. Acoramidis stabilizes TTR through hydrogen bonding as well as by bind­
Extended follow-up from the LTE study demonstrated a 41.2% rela­ ing to thyroxine-binding sites.45,46 Acoramidis has been reported to be
tive risk reduction in mortality in patients initially treated with tafamidis slightly more potent as a stabilizer than tafamidis and substantially more
80 mg in ATTR-ACT compared to those initially treated with placebo potent than diflunisal at a 10 µM plasma concentration.44
and switched to tafamidis during LTE, highlighting the importance of ATTRIBUTE-CM trial compared acoramidis to placebo in 632 pa­
early therapy.29 Moreover, combination of ATTR-ACT with LTE data tients with ATTR-CM (Table 1).47 The study had two parts with two
showed improved survival after 5 years among patients with NYHA primary endpoints. Part A’s primary endpoint, change from baseline

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III who initially received tafamidis 80 mg compared to those who initially to Month 12 in 6MWT, did not differ between groups while the pri­
received placebo, confirming that patients with advanced disease also mary endpoint of Part B, a hierarchical analysis of all-cause mortality,
benefit from tafamidis in the long term.30 Tafamidis was also recently cumulative frequency of CV hospitalizations, change in NTproBNP,
evaluated in patients ≥80 years who participated in ATTR-ACT. and change in 6MWT at 30 months, was in favour of acoramidis.
Albeit the group of patients was limited (n = 88), patients receiving ta­ Difference in all-cause mortality was not statistically significant between
famidis 80 mg during ATTR-ACT exhibited improved 6MWT distance, groups, despite an observed 25% relative reduction in all-cause mortal­
NTproBNP, and KCCQ than those receiving placebo.31 Moreover, pa­ ity with acoramidis. In contrast, frequency of CV hospitalizations was
tients ≥80 years treated continuously with tafamidis trended towards significantly reduced in patients receiving acoramidis with a relative re­
longer median survival (45 vs. 27 months; P = .15) than those initially duction approaching 50% (P < .0001). Other secondary endpoints like
treated with placebo in ATTR-ACT.31 NTproBNP, KCCQ, and 6MWT were also favourable affected by acor­
ATTR-ACT results lead to approval of tafamidis as the first specific amidis but the magnitude of the differences observed in these
ATTR-CM therapy. Tafamidis was also incorporated to the 2021 ESC parameters between acoramidis and placebo was less than in
HF guidelines for the treatment of ATTR-CM and NYHA class I or II to ATTR-ACT, likely attributable to differences in the populations studied.
reduce symptoms, CV hospitalizations, and mortality as a class I recom­ Acoramidis had a side effect profile similar to placebo. Of note, patients
mendation. The 2022 ACC/AHA/HFSA guidelines also recommend ta­ with NYHA III receiving acoramidis did not show increased hospitaliza­
famidis for selected patients with NYHA class III.32 tions. Lastly, time to first event of all-cause mortality or CV hospitaliza­
Since approval, real-life data have demonstrated the association be­ tion showed a relative reduction of 36% with a NNT of 7 at 30
tween tafamidis and a longer median time to HF decompensation, car­ months.48
diac transplant, or death.33
Nonetheless, tafamidis has an unfavourable cost analysis with its high
price limiting its access in many countries.34,35 Comparing stabilizers
Additional data on the role of tafamidis on biomarkers and imaging Two stabilizers, tafamidis and acoramidis, have demonstrated benefit in
parameters are emerging. Tafamidis slows the rise in NTproBNP and randomized clinical trials. Both drugs have shown an excellent safety
troponin T levels,36 and attenuates LV systolic and diastolic dysfunc­ profile with curves of all-cause mortality diverging similarly at 18–19
tion.37,38 Recent data also suggest that tafamidis could decrease cardiac months (Table 2).
uptake on scintigraphy in some individuals,39 despite cardiovascular Despite those similarities, inclusion criteria had important differ­
magnetic resonance (CMR) data have reported unchanged native T1 ences and likely account for the discrepancies found in the clinical end­
and extracellular volume (ECV) values after 1 year of treatment.40 points. Patients enrolled in ATTRibute-CM had a less advanced
Finally, there are concerns about the interaction between tafamidis disease with lower proportion of patients with NYHA III or ATTRv.
and statins and data are lacking in nonagenarians and in those with Furthermore, NTproBNP inclusion threshold was lower, and the re­
eGFR <25 mL/min/1.73 m2. quired 6MWT distance longer favouring inclusion of less advanced pa­
tients (Table 2).
Diflunisal ATTR-CM patients diagnosed nowadays have a better prognosis
Diflunisal is a nonsteroidal anti-inflammatory drug that also binds to the even in the absence of specific therapies due to earlier diagnosis and
T4-binding site preventing TTR dissociation and that is available in many better overall treatment,49 making it difficult to compare clinical trials
countries.41 Despite its stabilizing properties, diflunisal has potential conducted in different eras.
side effects given its anti-inflammatory nature including worsening of Although comparisons between trials are confounded by the differ­
hypertension, renal dysfunction, gastrointestinal bleeding, and HF ing populations, relative risk reduction in mortality was similar in both
decompensation. trials, whereas acoramidis demonstrated larger reduction in CV hospi­
Data of ATTR-CM patients treated with diflunisal come from single- talizations. Regarding changes in 6MWT and biomarkers, differences
centre studies and include limited number of patients.42,43 Interestingly, took longer to appear with acoramidis compared to tafamidis while dif­
several studies have shown clinical and echocardiography stability and ferences in KCCQ appeared at similar timepoints with both drugs des­
even improved survival in ATTR-CM patients receiving diflunisal pite the magnitude of the benefit being larger in ATTR-ACT.
250 mg twice daily.42,43 Of note, discontinuation rate was high ranging
from 23% to around 40% during initial years of treatment and variable
rates of renal function worsening and gastrointestinal side effects have Transthyretin suppressors
been reported.42,43 Reduction of TTR levels can be achieved in ATTR-CM either by genetic
Diflunisal in vitro stabilization seems to be inferior to other sta­ silencing or through gene editing. Transthyretin gene silencers have
bilizers44 but is an affordable drug that could be an option when been approved for several years for ATTRv with polyneuropathy,
other stabilizers are not accessible. In any case, a careful selection and data of cardiac efficacy are emerging. In contrast, gene editing has
of patients and close monitoring of renal function are been used in a very limited number of patients and the phase 3 clinical
recommended. trial has been initiated recently.
 6
Table 1 Transthyretin cardiac amyloidosis clinical trials

Mechanism of Route Trial and n Key inclusion criteria Key exclusion criteria Concomitant Primary endpoint Results and status
action therapy
...................................................................................................................................................................................................................................................
Tafamidis Stabilizer Oral ATTR-ACT • 18–90 years • NYHA IV • Diflunisal not Hierarchical all-cause Positive
Phase III • Invasive diagnosis of • eGFR < 25 mL/min/ permitted mortality and Drug approved in
(n = 441) ATTR-CM 1.73 m2 frequency of several countries
• IVS >12 mm • Liver transaminase >2 CV-related
• History of HF: previous HF times upper limit hospitalizations
admission or volume • Severe malnutrition
overload requiring (mBMI <600)
diuretics
• NTproBNP >600 pg/mL
• Distance on 6MWT
>100 m
Acoramidis Stabilizer Oral ATTRibute-CM • 18–90 years • Likely heart • Tafamidis allowed Part A: 6MWT at 12 Part A: negative
Phase III • Invasive or non-invasive transplantation within a after initial 12 months Part B: positive
(n = 632) diagnosis of ATTR-CM year months Part B: hierarchical Drug approved by
• History of HF: previous HF • ALT/AST >2 times and • Diflunisal not combination of FDA and under
admission or volume bilirubin >3 times the permitted mortality, CV evaluation by EMA
overload requiring upper limit hospitalizations,
diuretics • NTproBNP > 8500 pg/ NTproBNP, and
• NTproBNP >300 pg/mL mL 6MWT
• Distance on 6MWT • eGFR <15 mL/min/
>150 m 1.73 m2
Diflunisal Stabilizer Oral No randomized trial in Improved survival and
TTR clinical and
cardiomyopathy echocardiography
stability in
retrospective
observational
single-centre
studies
Patisiran Gene silencer IV APOLLO-B • 18–85 years • NYHA IV • Tafamidis allowed 6MWT at 12 months Results positive
(siRNA, 1st Q3 weeks Phase III • Invasive and non-invasive • NYHA III and NAC Stage • Diflunisal not 2°: KCCQ-OS at 12 Not approved by
generation) (n = 360) diagnosis of ATTR-CM 3 (NTproBNP >3000 pg/ permitted months FDA for
• IVS >12 mm mL and eGFR <45 mL/ ATTR-CM
• History of HF min/1.73 m2) Not evaluated by
• < 150 m on 6MWT EMA
• Polyneuropathy PND ≥ II

Continued
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Table 1 Continued

Mechanism of Route Trial and n Key inclusion criteria Key exclusion criteria Concomitant Primary endpoint Results and status
action therapy
...................................................................................................................................................................................................................................................
Vutrisiran Gene silencer SC HELIOS-B • 18–85 years • NYHA IV • Tafamidis allowed Composite of all-cause Results positive
(siRNA, 2nd Q3 months Phase III • Invasive and non-invasive • NYHA III at high risk • Diflunisal not mortality and
generation) (n = 655) diagnosis of ATTR-CM • eGFR <30 mL/min/ permitted recurrent CV events
• HF: previous admission or 1.73 m2 at 33–36 months in
clinical evidence of HF • Polyneuropathy PND III the overall
or IV population and in
monotherapy
Transthyretin amyloid cardiomyopathy

(patients not on
tafamidis at
baseline)
Eplontersen Gene silencer SC Cardio-TTRansform • 18–90 years • Liver or heart • Tafamidis allowed Composite of CV Recruitment
(ASO, 2nd Q1 month Phase III • Invasive and non-invasive transplantation • Gene silencers not mortality and completed.
generation) (n = 1443) ATTR-CM diagnosis • Previous treatment with permitted. recurrent CV clinical Results expected in
• IVS >12 mm gene silencers events mid 2026
• NYHAs I–III • Current treatment with
diflunisal
Nexiguran Gene Silencer IV once MAGNITUDE • Medical history of HF • NYHA class IV • Stabilizers allowed Composite outcome Recruiting
ziclumeran (CRISPR) Phase III • HF symptoms optimally • Polyneuropathy stage IV • Gene silencers not of CV mortality and
(NTLA-2001) (n = 765) managed and clinically • RNA silencer within permitted CV events
stable within 28 days previous 12 months
• NTproBNP ≥1000 or • Liver failure
≥2000 pg/mL in AF • eGFR <30 mL/min/
1.73 m2
ALX2220 (NI006) Recombinant IV Phase I • Confirmed diagnosis of • Tafamidis allowed Safety and Positive. Preliminary
human anti-TTR Q4 weeks (n = 40) ATTR • Diflunisal not pharmacokinetic supporting efficacy
antibody • IVS >14 mm permitted profile data
• LVEF >40% Cardiac imaging Phase II and III
• NYHAs I–III parameters ongoing
• eGFR >30 mL/min/
1.73 m2
• NTproBNP 600–6000 pg/
mL

Continued
7

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 8
Table 1 Continued

Mechanism of Route Trial and n Key inclusion criteria Key exclusion criteria Concomitant Primary endpoint Results and status
action therapy
...................................................................................................................................................................................................................................................
ALX2220 (NI006) Recombinant IV DepleTTR-CM • Confirmed diagnosis of • Leptomeningeal • Stabilizers and gene ALX2220 was safe Recruiting
human anti-TTR Q4 weeks Phase III ATTR amyloidosis silencers permitted Total Occurrence of all
antibody (n = 1000) • IVS >11 mm for women • PND score IV cause mortality and
or >12 mm for men • LVEF < 30% CV clinical events
• NTproBNP > 2000 pg/ • eGFR <20 mL/min/
mL 1.73 m2
• Loop diuretics for at least
30 days prior to screening
• NYHAs II–IV
• Life expectancy >6
months
Coramitug Anti-TTR antibody IV Q4 Phase II • 18–85 years old • Prior organ transplant • Stabilizers and gene • Change in 6MWT Recruitment
weeks (n = 99) • IVS >12 mm • >120 kg silencers permitted and NTproBNP completed
• NYHAs II and III Results expected late
• NTproBNP >650 or 2025
>1000 pg/mL if AF
present
• 150–450 m in 6MWT
• eGFR >25 mL/min/
1.73 m2
AT-02 Pan-amyloid IV infusion Phase I Part 1: healthy volunteers • Stabilizers and gene • Safety, tolerability Recruiting
humanized Part 2: patients with silencers permitted and
IgG1-peptide systemic amyloidosis: • Maintenance with pharmacokinetics of
fusion reagent • 18–80 years old daratumumab rising doses of
• Confirmed AL, ATTR, or permitted in AL AT-02
other forms of
amyloidosis
• AL patients should have
VGPR or CR within 12
months
Part 3: patients with
systemic amyloidosis: same
criteria as Part 2 plus imaging
evidence of organ amyloid
deposits

ATTRwt, wild-type transthyretin amyloidosis; ATTRv, hereditary transthyretin amyloidosis; IVS, interventricular septum; HF, heart failure; 6MWT, 6-min walk test; NYHA, New York Heart Association; eGFR, estimated glomerular filtration rate;
mBMI, modified body mass index; CV, cardiovascular; AL, light chain amyloidosis; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TTR, transthyretin; ATTR-CM, transthyretin cardiac amyloidosis; KCCQ-OS, Kansas City
Questionnaire–Overall Summary; IV, intravenous; RNA, ribonucleic acid; LVEF, left ventricular ejection fraction.
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Transthyretin amyloid cardiomyopathy 9

Table 2 Comparison between clinical trials with tafamidis and acoramidis

ATTR-ACT ATTRibute-CM
......................................................................................................................................................................................
Compound Tafamidis Acoramidis
Mechanism of action Binds to the T4-binding site Promotes hydrogen bonding between the hydroxyl groups
of adjacent S117 residues and binds to the T4-binding site
Inclusion criteria • Invasive diagnosis • Invasive and non-invasive diagnosis

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• NTproBNP >600 pg/mL • NTproBNP >300 and <8500 pg/mL
• eGFR >30 mL/min/1.73 m2 • eGFR >15 mL/min/1.73 m2
• 6MWT >100 m • 6MWT >150 m
• Tafamidis permitted after the initial 12 months
Number of participants n = 441 n = 632
Primary endpoint Hierarchical all-cause mortality and frequency of CV-related Hierarchical death from any cause, CV-related
hospitalizations hospitalization, change in NTproBNP, and in 6MWT
Secondary endpoint • Change from baseline to Month 30 on the 6MWT • Death from any cause
• Change from baseline to Month 30 on KCCQ • Distance on 6MWT
• KCCQ score
• Serum TTR level
Duration (months) 30 30
Age, years 74 ± 7 77 ± 7
Gender (% males) 90.2 90.2
Race (% Black) 14.3 4.7
TTR genotype
ATTRwt 76% 90.3%
ATTRv 24% 9.7%
NYHA class
NYHA I 8.3% 10.8%
NYHA II 59.6% 72%
NYHA III 31.9% 17.2%
NTproBNP (ng/L) 3161 (1864.4–4825) 2326 (1278–3910)

TTR, transthyretin; eGFR, estimated glomerular filtration rate; 6MWT; 6-min walking test; ATTRwt, wild-type transthyretin amyloidosis; ATTRv, hereditary transthyretin amyloidosis;
NYHA, New York Heart Association; CV, cardiovascular; KCCQ-OS, Kansas City Questionnaire–Overall Summary.

Transthyretin silencers First-generation transthyretin gene

Transthyretin silencers have been developed to reduce TTR produc­ silencers
tion independently of the wild type or variant nature of TTR. Two dif­
Patisiran
ferent types of drugs have been studied:
Patisiran, a siRNA formulated as a lipid nanoparticle, was approved in
2018 for ATTRv with polyneuropathy following APOLLO-A trial,
• Small interfering RNAs (siRNAs) are double-stranded oligonucleo­
which showed that patisiran halted or even reversed the progression
tides containing sense and antisense strands. Within the cytoplasm,
of neuropathy at 18 months.51
siRNA promotes a complex that binds to the target messenger
Patients on patisiran receive intravenous infusions every 3 weeks and
RNA (mRNA) to form a RNA-induced silencing complex with subse­
must be premedicated to mitigate infusion reactions mediated by the
quent degradation of the mRNA.50
lipid nanoparticle delivery system.
• Antisense oligonucleotides (ASOs) are single-stranded molecules
Around half of the patients participating in APOLLO-A were consid­
that act mainly at the nucleus, binding to the target mRNA and pro­
ered to have cardiac involvement based on the presence of LV wall
moting its degradation.50
thickness ≥13 mm in the absence of hypertension and aortic stenosis.
In this group of patients, patisiran showed LV wall thickness reduction,
Both approaches have demonstrated to knockdown serum TTR le­ improvement in longitudinal global strain (LGS), and reduction of
vels. In both cases, daily vitamin A supplements are required. NTproBNP.52
10 Gonzalez-Lopez et al.

APOLLO-B was a phase III, placebo-controlled trial in which 360 pa­ stopped prematurely due to an increase in mortality,56 vutrisiran con­
tients with wild-type and hereditary ATTR-CM were randomized 1:1 to tains smaller dose and has longer dosing intervals.
patisiran or placebo during 12 months (Table 1).9 Vutrisiran was approved in ATTRv with polyneuropathy following
The study met its primary endpoints, demonstrating a lower decline in the results from HELIOS-A.57 Exploratory prespecified cardiac end­
the 6MWT and an increase in KCCQ score at 12 months with patisiran. points showed significant decreased NTproBNP levels and improve­
Although differences in 6MWT and KCCQ were statistically signifi­ ments in some echocardiographic parameters at 18 months both in
cant, U.S. Food and Drug Administration (FDA) did not approve pati­ the overall cohort and in the cardiac subpopulation (defined in the
siran for ATTR-CM because of concerns regarding the clinical same way as in APOLLO-A trial), compared with the external placebo

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meaningfulness of the effect based on the differences found in end­ group from APOLLO-A.58 It is worth mentioning that this definition
points: a median difference of 14.69 m in 6MWT and 3.7 points in probably does not capture all patients with cardiac amyloidosis59 and
KCCQ, below the minimal clinically significant difference of 30 m and could have limited the results as some patients who did not qualify
5 points. for the predefined subpopulation probably exhibited ATTR-CM.58
While APOLLO-B did not demonstrate significant benefits for the Interestingly, improvement in normalized LV total uptake and
secondary endpoint of a composite of death from any cause, CV events, heart-to-contralateral lung ratio were observed in approximately
and change in the 6MWT over 12 months, it provided evidence over two-thirds of patients who underwent serial scintigraphy at baseline
the short term for a beneficial effect of gene silencing in ATTR-CM. and at 18 months. Furthermore, Perugini grade was reduced or un­
Moreover, recent data have shown a sustained clinical benefit of patisir­ changed compared with baseline in 55/57 (96.5%) evaluable patients.58
an in the open-label extension of the trial at 24 months, demonstrating HELIOS-B, a phase III, randomized, double-blind, placebo-controlled
that what patients lose in terms of function and quality of life is not re­ multicentre study, has evaluated the efficacy and safety of vutrisiran in
gained.53 Given that the trial was only 12 months, larger differences may ATTR-CM. HELIOS-B enrolled 655 ATTR-CM patients with NYHAs I–
be expected over time in clinical outcomes. III, with 40% of participants on tafamidis at baseline (Table 1).60 The pri­
mary composite endpoint was a composite of all-cause mortality and
recurrent CV events at 33–36 months in the overall population and
Inotersen
in the monotherapy one (patients not taking tafamidis at baseline).
Inotersen is a first-generation ASO, administered subcutaneously every
Enrolled patients in HELIOS-B represent a contemporary cohort of pa­
week. Inotersen was approved for ATTRv with polyneuropathy follow­
tients with ATTR-CM, similar to ATTRIBUTE-CM, with male predom­
ing the positive results from NEURO-TTR.54 Approval was accompan­
inance (92.5%), median age of 76.5 years, and two-thirds of them in
ied by the requirement of regular and frequent platelet and renal
NYHA II (77.6%). Vutrisiran met its primary endpoint compared to pla­
function monitoring to control severe thrombocytopenia and glomer­
cebo in both the overall population [HR 0.72; 95% confidence interval
ulonephritis observed in the trial. These adverse events and the need of
(CI): 0.56–0.93; P = .01] and the population of patients without con­
frequent monitoring counterbalanced in most patients the advantages
comitant tafamidis (HR 0.67; 95% CI: 0.49–0.93; P = .02).
of subcutaneous administration.
Additionally, vutrisiran was associated with a lower decline in the dis­
From a cardiac perspective, no significant differences by LGS or
tance on 6MWT and KCCQ-OS at 30 months with a good safety
other echocardiographic variables were observed between patients
and tolerability profile.60
treated with inotersen and those receiving placebo in patients with car­
diomyopathy (same definition than in APOLLO-A). A small cohort of
33 patients with ATTR-CM either ATTRv or ATTRwt were treated Eplontersen
with inotersen in a single-centre, open-label protocol.55 Although Eplontersen is a novel GalNAc-conjugated ASO, with the same
follow-up was limited, preliminary findings of those patients who base sequence as inotersen but with enhanced liver uptake. It is
reached the 2- and 3-year time points included improvements in LV administered subcutaneously every 4 weeks. Eplontersen has demon­
mass at CMR and in 6MWT.55 With the advent of the second- strated favourable outcomes in ATTRv with polyneuropathy in
generation genetic silencers, it is most likely that inotersen will become NEURO-TTRansform.61 In the cardiomyopathy subgroup, defined by
obsolete and its production will be halted as has already occurred in the previous diagnosis or interventricular septum ≥13 mm in the absence
USA. of hypertension, eplontersen was associated with improvement in LV
ejection fraction and stroke volume from baseline to Week 65 while
other echocardiographic parameters remained stable compared with
Second-generation transthyretin genetic historical placebo group from NEURO-TTR despite notable differ­
silencers ences at baseline parameters between both groups.62
A second generation of subcutaneous TTR genetic silencers has been Efficacy of eplontersen for ATTR-CM is currently being studied in
developed, showing increased stability, higher liver distribution, and the CARDIO-TTRansform trial that has enrolled 1443 patients with
less non-hepatocyte exposure. Moreover, the mean knockdown of ser­ NYHAs I–III (Table 1). CARDIO-TTRansform is the largest trial con­
um TTR achieved is superior to the first generation of genetic silencers. ducted in ATTR-CM, with results expected by mid 2026. Its primary
composite endpoint includes CV mortality and recurrent CV events
Vutrisiran up to Week 140. Additionally, it includes CMR and scintigraphy sub-
studies to assess the effect of eplontersen on amyloid burden.
Vutrisiran is a siRNA conjugated to N-acetyl galactosamine (GalNAc)
conferring high affinity to hepatocytes. Advantages over patisiran in­
clude the subcutaneous quarterly administration and that it does not Transthyretin gene editing
require any premedication as it is not included in a lipid nanoparticle. Transthyretin amyloidosis is one of the first human diseases where clus­
Compared to revusiran, a first-generation siRNA conjugated to tered regularly interspaced short palindromic repeats (CRISPR)-Cas9
GalNAc, whose phase III trial in ATTR-CM, ENDEAVOUR, was technology has been applied.
Transthyretin amyloid cardiomyopathy 11

Nexiguran ziclumeran doses.10 NTproBNP levels also showed a dose-related decrease with
Nexiguran ziclumeran (Nex-Z), formerly NTLA-2001, is a CRISPR- a median reduction of around 58% at 12 months in patients receiving
Cas9-based gene therapy designed to treat ATTR by displaying liver- the higher doses.10
directed lipid nanoparticles that contain Streptococcus pyogenes Cas9 After these promising findings, a phase 3 trial, DepleTTR-CM has
mRNA and a TTR-specific sgRNA. The Cas9 mRNA is translated in been initiated. DepleTTR-CM plans to recruit 1000 patients with
the hepatocyte’s cytoplasm, and the formed Cas9 endonuclease inter­ ATTR-CM and NYHAs II–IV who will be randomized in a 1:1 fashion
acts with the TTR-specific sgRNA to form the Cas9-sgRNA ribonu­ to monthly intravenous infusions of ALX2220 or placebo for 24 to
cleoprotein. This complex enters the nucleus, where it unwinds 48 months. The primary endpoint is a composite of events of all-cause

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DNA and binds to DNA at the TTR gene to induce targeted DNA cleav­ mortality and CV events (Table 1).
age. Then, endogenous DNA repair introduces indel mutations in the
TTR gene that ultimately prevent TTR synthesis. Coramitug
Initial data have shown profound and long-lasting TTR knockdown, Coramitug, formerly NNC6019-0001 and previously PRX004, is a hu­
supporting its potential as a single-administration therapeutic option, manized monoclonal antibody that targets an epitope of TTR that is ex­
avoiding serial infusions or injections. Phase I open-label trial was a posed on monomeric, misfolded, and aggregated forms of TTR but
single-ascending dose study conducted initially in ATTRv with polyneur­ hidden in native circulating tetramers.
opathy and then expanded to ATTR-CM. Part 1 was successful, with no By specific binding, coramitug clears TTR amyloid deposits through
major side effects and a TTR knockdown of up to 90% by Day 28, which antibody-mediated phagocytosis and, in addition, it may prevent new
was maintained up to 4–6 months.8 Recently, additional data at 1 and 2 amyloid fibril formation.
years showed maintenance of similarly reduced TTR levels and good A phase I clinical trial showed that coramitug was safe and generally
safety profile.63 Part 2 of the phase I trial is an ongoing open-label, well tolerated in 21 patients with ATTRv. Moreover, a possible cardiac
dose expansion study to assess the effect on cardiac and neurological benefit was observed through LGS improvement in 7 patients.67
measures and will provide additional safety data. A phase II trial assessing its potential in ATTR-CM has recruited 99
MAGNITUDE, a phase III clinical trial, is currently recruiting patients who have been randomized to receive coramitug at doses of
ATTR-CM patients (Table 1). A total of 765 subjects will be randomized 10 and 60 mg/kg, or placebo. Patients receive monthly infusions for
2:1 to receive nexiguran ziclumeran or placebo with concomitant treat­ 12 months, and the primary outcomes are the change in 6MWT and
ment with stabilizers being allowed whereas not with genetic silencers. NTproBNP (Table 1). Results are expected in late 2025.
The primary endpoint is a composite of CV mortality and CV events
and the duration of the trial depends on event rates. AT-02
AT-02 is a humanized IgG1-peptide fusion reagent where the
Removers pan-amyloid reactive peptide p5R is fused to the C-terminal of the light
It was considered that amyloid fibrils were insoluble, with amyloid de­ chain. It binds to all types of amyloid deposits as peptide p5R binds the
posits evoking very little endogenous tissue reaction and being resistant ubiquitous hypersulfated glycosaminoglycans and fibrils via electrostatic
to enzymatic degradation. interactions. The same peptide technology with the AT-01 imaging
Although natural amyloid clearance was thought to occur in agent (24I-evuzamitide) has shown uptake in key organs in multiple
other cardiac amyloidosis, the process had not been documented in amyloid types in phase 1 and 2 clinical trials.68,69 Through the addition
ATTR-CM until recently. Initial case reports with CMR followed by of the humanized IgG antibody, AT-02 promotes macrophage-
some scintigraphy studies of patients treated with both stabilizers mediated amyloid clearance and enhances amyloid phagocytosis.70
and genetic silencers revitalized the concept that removing TTR amyl­ Following successful animal data, phase I and II trials are currently re­
oid was possible.64 Three patients with spontaneous clearance of amyl­ cruiting healthy volunteers and patients with systemic amyloidosis in­
oid cardiac deposits who exhibited anti-amyloid antibodies provided cluding ATTR-CM.
further support to the possibility of enhancing amyloid removal.65
Pending questions
ALX2220
ALX2220, formerly NI006, is a recombinant human antibody that binds As the new disease-modifying drugs approach clinical use, several ques­
to a cryptic epitope that is exposed in misfolded TTR oligomers and ag­ tions arise (Figure 5).
gregated TTR fibrils.66
In preclinical studies, ALX2220 has shown high affinity binding to Assessing response to therapy
ATTR fibrils facilitating their elimination via activation of phagocytic Monitoring response is a clear unmet need in ATTR-CM. In the absence
cells.66 of longitudinal data, monitoring and progression criteria for ATTR-CM
Phase I clinical trial recruited 40 patients, predominantly ATTRwt were proposed in 2021.71 A set of 11 measurable features across 3 do­
(83%), with those receiving ALX2220, apparently, at a more advanced mains were considered: (i) clinical and functional endpoints, (ii) biomar­
stage.10 No serious adverse events were reported while mild or mod­ kers and laboratory markers, and (iii) imaging and electrocardiographic
erate side effects observed included cytokine release syndrome, non- parameters.71 Progression in one marker from each domain is required
severe thrombocytopenia, and musculoskeletal symptoms, which to consider disease progression. Although several recent studies have
have been presumed to be associated with the activation of phagocytic applied these criteria to study disease progression on patients treated
immune cells aimed at musculoskeletal TTR deposits.10 with tafamidis,72,73 it is unknown whether these criteria could be used
The phase I trial also provided promising results in terms of efficacy. to assess response or failure to disease-modifying drugs.
Cardiovascular magnetic resonance and scintigraphy data indicated a A recent multicentre study has proposed and validated the increase
dose-related reduction of ECV and tracer uptake with the highest at 1 year of NTproBNP (increase >700 ng/L and >30%) and outpatient
12 Gonzalez-Lopez et al.

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Figure 5 Unresolved questions regarding transthyretin cardiac amyloidosis-specific therapies

Table 3 Combination therapies in transthyretin cardiac amyloidosis clinical trials

Study Number of Combination therapy Participants with Participants with multiple

participants allowed concomitant tafamidis specific therapies
......................................................................................................................................................................................
ATTRIBUTE-CM 632 (611 primary analysis) Acoramidis + tafamidis 107 (17.5%) 61 (14.9%)
APOLLO-B 360 (359 efficacy and safety Patisiran + tafamidis 99 (27.6%) 51 (14.2%)
analyses)
HELIOS-B 655 Vutrisiran + tafamidis 345 (52.7%) 174 (26.6%)
Cardio-TTRansform 1443 Eplontersen + tafamidis No limit Unknown

diuretic intensification as markers of disease progression.74 Moreover, circulating TTR can misfold and promote fibril formation. Although
an absolute (>35 m) and relative (>5%) reduction of distance at mean reduction of TTR levels achieved with second-generation silen­
6MWT at 1 year predicted mortality in a single-centre study of 1118 cers and gene editing is around 80%–90%, this value could be lower
patients.75 Also, echocardiographic worsening of mitral and tricuspid in certain patients. Moreover, it is unknown if there is an optimal knock­
regurgitation and stroke volume have been described to be associated down (or stabilization) value beyond which fibril formation is halted.
with worse prognosis.76 No study has examined these markers accord­ Therefore, it is unknown if the possible synergistic effect of combining
ing to any treatment yet, and it is unknown if these parameters could be treatments would translate into improved clinical outcomes. This ques­
used to guide management and switch from one specific treatment to tion would be partially answered by analysing gene silencing clinical trials
another. that have allowed background standard treatment including tafamidis.
Lastly, although there are not solid data with scintigraphy and CMR Unfortunately, the number of patients on tafamidis and the duration
to asses progression in ATTR-CM, the relevance of both techniques has of therapy are highly heterogeneous across studies complicating mean­
increased lately in other types of amyloidosis and in recent ATTR-CM ingful conclusions (Table 3).
trials to assess response to new therapies.10,58 Accordingly, these tech­ So far, the most solid data available about combined treatment
niques could have an important role in the future to determine treat­ arises from subgroup analysis of APOLLO-B where patisiran was
ment response. not superior to placebo on 6MWT and KCCQ among the 90 partici­
pants who received tafamidis at baseline.77 In ATTRIBUTE-CM, tafa­
midis was allowed after the initial 12 months and while 14.9% initiated
Combined treatment tafamidis in the acoramidis group during the study, data point towards
Combination of multiple specific therapies might enhance therapeutic absence of benefit on combining both stabilizers.47 In HELIOS-B, 40%
efficacy, through targeting the amyloidogenic cascade at several points. of participants had tafamidis at baseline and 22% of those receiving vu­
Simultaneous targeting of TTR production and stabilization may have a trisiran in monotherapy started tafamidis during follow-up.60 The trial
synergistic effect as TTR knockdown is not complete and remaining was not powered to show differences according to baseline tafamidis
Transthyretin amyloid cardiomyopathy 13

use, and patients were not randomly assigned to the stabilizer, there­ retrospective study, they provide support to consider early initiation
fore not allowing for a valid comparison of vutrisiran with tafamidis or of stabilizers in asymptomatic ATTR-CM patients.
of combination therapy with monotherapy.60 Another group of patients that might benefit from preventive treat­
The trial that seems most prepared to address this question is ment is asymptomatic ATTRv variant carriers without signs of the dis­
Cardio-TTRansform that has enrolled enough participants to under­ ease. A placebo-controlled trial with acoramidis (ACT-EARLY) is
take subgroup analysis. Nevertheless, even if combination therapy has currently being conducted in this population and will enrol 582 healthy
a role in the treatment of ATTR-CM, costs might turn combination TTR variant carriers (NCT06563895).85
treatment prohibitory and inaccessible for most patients.

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Long-term safety of transthyretin Conclusions
depletion ATTR-CM constitutes an example of precision medicine applied to car­
Within an experience of 6–8 years now with first-generation gene silen­ diology. A better understanding of the pathophysiology of ATTR has
cers, short to medium term of TTR knockdown appears safe.51,54 boosted the development of several therapeutic options that leverage
Long-term safety remains unknown though, and concerns increase different mechanism of action. The future looks bright for ATTR-CM as
with the irreversibility of gene editing. several therapeutic alternatives are turning an untreatable disease into a
From a physiological point of view, it seems there are other trans­ treatable and potentially reversible one.
porters that compensate TTR function as a carrier of vitamin A and
thyroxine. Transthyretin knockdown does not appear to affect
thyroid function, and vitamin A supplementation prevents ocular Supplementary data
manifestations. Supplementary data are not available at European Heart Journal online.
Nevertheless, it has been speculated that TTR might have a pro­
tective role at the central nervous system. Transthyretin knockdown
in mice resulted in memory impairment compared to age-matched
mice and absence of TTR in rats accelerated aging cognitive
Declarations
decline.78,79 In patients with cerebral infarction, serum TTR Disclosure of Interest
levels were an independent predictor of good clinical outcomes.80 E.G.-L. reports speaking fees from Pfizer, Eidos, and Alnylam; consulting
Additionally, TTR seems to modulate food intake and body weight fees from Pfizer, Akcea, Novo Nordisk, Alnylam, AstraZeneca, and
in animal models and retinol binding protein 4 is linked to insulin re­ Proclara. M.S.M. reports grants from Alnylam, BridgeBio, Attralus,
sistance, diabetes, and metabolic syndrome.81,82 Therefore, long- Intellia, and Ionis and personal fees from Alnylam, Novo Nordisk,
term safety of TTR depletion is still uncertain and long-term studies Astra Zeneca, Ionis, and Intellia. P.G.-P. reports speaking fees from
are needed. Alnylam Pharmaceuticals, AstraZeneca, BridgeBio, Intellia, Ionis
Pharmaceuticals, Novo Nordisk, and Pfizer and consulting fees from
Central nervous system and ocular Alexion, Alnylam Pharmaceuticals, AstraZeneca, ATTRalus, Bayer,
involvement BridgeBio, Intellia, Ionis Pharmaceuticals, Pfizer, Neuroimmune, and
As prognosis of ATTRv patients improves, amyloid deposits at central Novo Nordisk. E.G.-L. and P.G.-P. report research/educational support
nervous system and intraocular may become more common due to to their institution from Pfizer, BridgeBio, Novo Nordisk, AstraZeneca,
choroid plexus and retinal TTR production, setting a new challenge Intellia, and Alnylam Pharmaceuticals.
for management. Among the approved drugs for ATTRv, tafamidis is
the only that has demonstrated to cross the blood–brain barrier des­ Data Availability
pite showing low concentrations in cerebrospinal fluid.83 No data were generated or analysed for this manuscript.

Specific treatment in presymptomatic Funding

patients E.G.-L. and P.G.-P. are supported by Instituto de Salud Carlos III
Advances in non-invasive diagnosis, the spread of knowledge about through the projects ‘PI18/0765, PI20/01379 & PI24/02093’ (co-funded
ATTR-CM, and a closer follow-up of ATTRv patients with polyneurop­ by European Regional Development Fund/European Social Fund ‘A way
athy and asymptomatic genetic carriers have translated into the diagno­ to make Europe’/‘Investing in your future’). CNIC is supported by the
sis of patients who do not exhibit HF at time of ATTR-CM diagnosis. ISCIII, MCIN, the PROCNIC Foundation, and the Severo Ochoa grant
This new population of patients is less prone to have events during (CEX2020-001041-S). M.S.M. reports grant support from NIH
follow-up, and new studies could struggle to show differences in clinical R01HL139671 and AG081582
outcomes.
Clinical trials have focused on patients with overt HF with the cur­
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