Cardiac Amyloidosis: Pathogenesis, Diagnosis, and Treatment

Background: The administrative prevalence of cardiac amyloidosis is approximately 50 per 100 000 person-years. The pathophysiology of amyloidosis involves a misfolding of proteins with a beta-pleated sheet structure. This leads to the deposition of insoluble fibrils in the interstitium, which, in turn, impair organ function and cause a variety of diseases. Systemic types are the most common, especially light-chain (AL) and transthyretin (ATTR) amyloidosis with cardiac involvement. In this article, we present the diagnostic evaluation of amyloidosis and recent developments in its treatment.

Methods: This review is based on publications retrieved by a selective search in PubMed for registry studies, meta-analyses, randomized controlled trials, systematic reviews, guidelines, and current position papers on “cardiac amyloidosis,” “ATTR amyloidosis,” “cardiac amyloidosis epidemiology,” “cardiac amyloidosis treatment,” and “ATTR amyloidosis treatment.”

Results: Cardiac amyloidosis markedly impairs cardiac function and carries a poor prognosis as well as elevated mortality. The diagnosis is mainly based on specialized imaging studies including echocardiography, cardiac magnetic resonance imaging, and scintigraphy. The goal of treatment is to slow amyloid deposition. In ATTR amyloidosis, transthyretin stabilizers or RNA silencers can stabilize the clinical course: the use of tafamidis has been found to be associated with better outcomes and lower overall mortality at 30 months compared with placebo (HR 0.70 [0.51; 0.96]). Vutrisiran also lowers overall mortality and reduces recurrent cardiovascular events compared to placebo (HR 0.72 [0.56; 0.93]). Cardiac complications and comorbidities can be treated, depending on left ventricular function and drug tolerability, with SGLT2 inhibitors, beta-blockers, and mineralocorticoid receptor antagonists, among other drugs.

Conclusion: Advanced cardiac amyloidosis carries a poor prognosis; early diagnosis and targeted treatment are of decisive importance. Better outcomes are now possible with the aid of improved imaging methods, disease-modifying treatment options, and the treatment of cardiac complications. Further approaches are now being studied.

Cite this as: Beckmann S, Akin I, Haghikia A, Rassaf T, Hamdani N, El-Battrawy I: Cardiac Amyloidosis: Pathogenesis, diagnosis, and treatment. Dtsch Arztebl Int 2026; 123: 447–52. DOI: 10.3238/arztebl.m2026.0088

Amyloidosis is a progressive disease in which misfolded proteins are deposited in the interstitium as insoluble fibrils rich in β-sheets. Organ tropism is determined by protein-specific properties of the precursor protein and local tissue conditions that promote fibril formation and growth, such as a high local protein concentration, an acidic environment, or interaction with matrix components (1). The main types affecting the heart are transthyretin (ATTR) amyloidosis and light-chain (AL) amyloidosis. Myocardial amyloid deposition typically causes restrictive cardiomyopathy, which presents as heart failure with preserved ejection fraction (HFpEF).

Retrospective data from Germany (2009–2018) reveal a steady increase in administrative prevalence (from 15.5 to 47.6 per 100,000 person-years) and administrative incidence (from 4.8 to 11.6 per 100,000 person-years). Reasons for this increase include the establishment of low-threshold diagnostic pathways and increasing medical attention to the condition, as exemplified by the position paper of the German Society of Cardiology – Heart and Circulatory Research (DGK) (2). Data from the Federal Statistical Office in Germany also reveal a marked rise in the disease burden of organ-limited amyloidosis (ICD-10 E85.4) as reflected in hospitalizations, from 221 cases (2000) to 1,515 cases (2023) (3). According to a systematic review and meta-analysis by Aimo et al. elevated prevalence is found among patients in high-risk groups including those with HFpEF, carpal tunnel syndrome, or severe aortic valve stenosis (4). There is typically a delay between the initial suspicion of cardiac amyloidosis and its definitive diagnosis; this suggests that it may underdiagnosed (4, 5). Multiple articles on cardiac amyloidosis have appeared to date in Deutsches Ärzteblatt International (6, 7). In the meantime, tafamidis and acoramidis have been approved for ATTR cardiomyopathy (ATTR-CM), and the RNA-silencing approach with vutrisiran has been introduced. In this narrative review, we provide practice-oriented information on the pathophysiology, diagnosis, and treatment of cardiac amyloidosis, including specific therapies, accompanying drug treatment, and follow-up care.

Methods

This narrative review of the diagnosis and treatment of cardiac amyloidosis, focusing on ATTR-CM, is based on pertinent publications (1989–2025) retrieved by a selective search in PubMed for randomized controlled trials, registry studies, meta-analyses, and systematic reviews. The keywords included “cardiac amyloidosis,” “ATTR amyloidosis,” “cardiac amyloidosis epidemiology,” “cardiac amyloidosis treatment,” and “ATTR amyloidosis treatment.” The updated versions of the guidelines and consensus statements of the European Society of Cardiology (ESC) (2021) and the German Society of Cardiology (DGK) (2023) (8, 9) were considered as well.

ATTR amyloidosis and its main differential diagnoses

ATTR amyloidosis

ATTR amyloidosis arises from misfolding of the transport protein transthyretin (TTR), which is produced in the liver. If the physiological tetramer conformation becomes unstable, TTR dissociates into its subunits. This can expose surfaces prone to aggregation, which, in turn, promotes misfolding and the formation of β-sheet-rich amyloid fibrils (1). There are both a hereditary form (ATTRv; germline mutation in the TTR gene) and a non-hereditary wild-type form (ATTRwt without a pathogenic variant in the TTR gene). In ATTRwt, old age is the main risk factor, as oxidative changes and declining proteostasis promote misfolding and aggregation. The median survival of patients with wild-type ATTR-CM without treatment is ca. 3.5 years (10). The hereditary form is caused by autosomal-dominant germline mutations in the TTR gene that impair tetramer stability (1). To date, over 100 different mutations are known; prevalent genotypes vary by region, with variable effects on mortality (11). Hereditary ATTR amyloidosis is rare. In earlier studies, it was estimated that 5,000–10,000 people worldwide suffer from ATTR polyneuropathy (12); more recent estimates are lacking.

Differential diagnosis

AL amyloidosis is an important differential diagnosis of ATTR amyloidosis; because AL amyloidosis progresses rapidly, its detection should be followed by the immediate initiation of hematological treatment. It is caused by a plasma cell dyscrasia (multiple myeloma or monoclonal gammopathy of undetermined significance [MGUS]), with deposition of monoclonal light chains (kappa/lambda) as insoluble fibrils (13). In the heart, these are ingested by myocytes, leading to cellular dysfunction and, potentially, myocardial damage (14). Cardiac involvement is common and has a major effect on the clinical outcome (8). Staging (risk stratification) is with the Mayo scale, based on troponin T, NT-proBNP, and the free light chain ratio: classes I–IV are associated with median survival times of 94, 40, 14, and 6 months, respectively (15). Another differential diagnosis is systemic AA amyloidosis, arising from serum amyloid A in the presence of chronic inflammation, which usually predominantly affects the kidneys. Cardiac AA amyloidosis is rare (8).

Symptoms and diagnostic evaluation

In clinical practice, cardiac amyloidosis is rarely encountered and must be actively sought. Manifest heart failure is often preceded by seemingly non-cardiac signs. Early cardiac involvement often presents with heart failure with preserved ejection fraction (HFpEF). In this condition, the ejection fraction is still normal, but myocardial stiffness impairs diastolic filling. In a screening study, cardiac amyloidosis was detected in approximately 12% of patients with HFpEF in a selected high-risk cohort (4). Warning signs that should arouse suspicion early on are listed in eTable 1.

The physician should suspect this disease, not because of a single symptom, but rather because of a combination of symptoms, historical clues, and test findings, i.e., heart failure symptoms plus extracardiac red flags or typical cardiac discrepancies (8). There are two clinically relevant clusters of findings that should arouse suspicion of cardiac amyloidosis:

• Cluster 1: cardiac and systemic red flags
• aortic valve stenosis in patients aged 65 and above
• rapidly progressive dyspnea/decline in exercise tolerance and/or edema
• bilateral carpal tunnel syndrome, spinal canal stenosis, biceps tendon rupture
• peripheral polyneuropathy, autonomic dysfunction
• Cluster 2: cardiac and structural/functional discrepancies
• ,left ventricular (LV) wall thickening ≥ 12 mm of no other known cause
• disproportionately elevated NT-proBNP in comparison with the clinical severity of heart failure; chronically elevated troponin levels
• pseudo-infarction pattern; low voltage-to-mass ratio

Other, less specific manifestations of systemic involvement, including bowel irregularities, neuropathic pain, muscle weakness, and general fatigue, should be considered in the overall clinical context.

Stepwise diagnostic evaluation of cardiac amyloidosis:

If cardiac amyloidosis is suspected, NT-proBNP and high-sensitivity troponin (hsTnT) should be measured to assess cardiac involvement. Low levels (< 180 ng/L NT-proBNP—negative predictive value [NPV] 92%; < 14 ng/L hs-TnT [NPV 91%]) imply that there is no clinically relevant cardiac involvement (16). High levels, however, are nonspecific and should be interpreted in conjunction with imaging findings.

If suspicion persists, AL amyloidosis should be ruled out with immunofixation (serum/urine) and measurement of free light chains, given the therapeutic urgency of this condition if present. After a negative result, further diagnostic testing can focus on ATTR amyloidosis (17, 18).

The first imaging study is echocardiography. Key findings include left ventricular wall thickening (≥ 12 mm) of no other known cause, indicating myocardial infiltration (8). Associated findings may include a granular sparkling myocardium as well as pleural and pericardial effusions (8, 19). In early stages, subtle functional changes can be detected, such as diastolic dysfunction with preserved systolic ejection fraction (8, 20). Strain analysis is more sensitive, revealing reduced longitudinal movement of the heart muscle with relative apical sparing (21, eFigure 1).

Figure 1

The treatment of cardiac complications and comorbidities in patients with cardiac amyloidosis: modified from (18) ATTRwt, wild-type transthyretin amyloidosis; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; LVAD, left ventricular assist device; PPM, permanent pacemaker; SGLT, sodium-glucose cotransporter; TAVI, transcatheter aortic valve implantation

eFigure 1

a) This GLS analysis of a patient with early-stage left ventricular hypertrophy shows a cherry-on-top phenomenon with apical sparing. b) E is much larger than A, consistent with a restrictive filling disorder. c) E/E' lateral 19 and thus E/E' averaged 23, consistent with an elevated filling pressure; d) E/E' septal 29; e) septal myocardial hypertrophy with increased echogenicity of the septal myocardium; f) ECG with classic low voltage

Cardiac magnetic resonance imaging (MRI) is used for further characterization of myocardial infiltration, or when the echocardiographic findings are unclear. It enables the detailed visualization of amyloid deposition and the extent of infiltration (Figure). Typically, diffuse or transmural contrast enhancement is seen in the myocardium (8, 22).

Figure

Figure: Cardiac magnetic resonance imaging of a patient with amy - loidosis and marked left ventricular hypertrophy a) Short-axis view (cine-MRI) showing concentric thickening of the left ventricular wall; b) four-chamber view (cine-MRI) showing marked left ventricular hypertrophy and biatrial dilatation.

If there is high clinical suspicion, bone scintigraphy with 99mTc-labeled phosphate tracers is a key procedure for noninvasive confirmation of the diagnosis of ATTR cardiomyopathy. Marked tracer uptake indicates cardiac amyloid deposition(23) (eFigure 2). If the planar scan is positive, single-photon emission computed tomography (SPECT) should be performed in addition for the more precise localization of myocardial tracer uptake, which increases diagnostic certainty (8) (eFigure 2). If no monoclonal proteins are detected, ATTR amyloidosis can be diagnosed with high likelihood, generally obviating the need for cardiac biopsy (24).

eFigure 2

Planar scintigraphy and SPECT image of the 99mTc-DPD scan showing high-grade myocardial uptake a) Planar scintigraphy showing marked tracer uptake in the heart, corresponding to a Perugini score of 3 (heart = skeleton). b) Thoracic SPECT after 99mTc-DPD scintigraphy: volume-reconstructed overview of tracer distribution in the thorax; cross-sectional images in the transverse, sagittal, and coronal planes are shown as well. c) The serial transverse sections reveal left ventricular predominance of myocardial tracer uptake and confirm the cardiac origin of the planar excess uptake.

An endomyocardial biopsy is reserved for cases in which light-chain testing is positive or noninvasive diagnostic tests do not yield a clear result (17). Biopsy enables the direct detection of amyloid deposits. It is an invasive procedure whose complications include cardiac arrhythmia, bleeding with pericardial effusion, and, rarely, pericardial tamponade or myocardial infarction. It should only be carried out after meticulous assessment of the benefits and risks. The risks tend to be high in patients with ATTR, who are often elderly and multimorbid.

Genetic testing

If ATTR is confirmed and its subclassification is unclear, molecular genetic analysis of the TTR gene is recommended to differentiate between ATTRwt and ATTRv (8). Hereditary variants are rare (estimated prevalence < 1 : 100,000 in Europe, with regional variations) (25) but can present at any age and indicate genetic counseling and screening of family members. Their cardiac manifestations are treated as in non-hereditary ATTR cardiomyopathy. 6.6% of adults who were referred to a genetic testing program because of suspected ATTRv and/or family history were found to have a pathogenic TTR variant (26).

Treatment

The treatment of cardiac amyloidosis rests on two pillars: slowing of amyloid deposition in the myocardium and management of the complications of the disease (18) (Figure). Symptomatic treatment mainly consists of meticulous volume control to maintain euvolemia. Loop diuretics are the most important drug class for this purpose but must be titrated cautiously because of the restrictive hemodynamic disturbance, which often leads to orthostatic hypotension (27).

Conventional neurohormonal therapy must be considered on a case-by-case basis. Beta-blockers are generally indicated for patients with a left ventricular ejection fraction (LVEF) of ≤ 40%, but they may affect symptoms adversely in patients cardiac amyloidosis, because the cardiac output depends more strongly on heart rate when the stroke volume is fixed. Patients with amyloidosis and a reduced LVEF ≤ 40% survive significantly longer on beta-blocker therapy according to observational data (hazard ratio [HR] 0.61, 95% confidence interval [0.45; 0.83], p = 0.002), but a general improvement of outcome could not be shown (28).

ACE inhibitors, angiotensin II receptor blockers, and angiotensin receptor-neprilysin inhibitors are part of standard therapy for an LVEF ≤ 40%, but they are nonetheless not usually recommended for patients with cardiac amyloidosis. These drugs cause peripheral vasodilation, which can, in turn, cause hypotension, as there can be no more than a limited compensatory increase in stroke volume. A consistent prolongation of survival has not been shown (28).

Mineralocorticoid receptor antagonists are generally indicated for an LVEF ≤ 40% and are hemodynamically well tolerated even in patients with cardiac amyloidosis. In a retrospective analysis, they were associated with lower overall mortality in patients with preserved systolic function (28). SGLT2 inhibitors were also well tolerated in patients with ATTR cardiac amyloidosis (discontinuation rate 4.5%), likely because they only mildly lower the blood pressure. SGLT2 inhibitors also lowered the risk of hospitalization for heart failure (HR 0.57, 95% confidence interval [0.37; 0.89], p = 0.01) and cardiovascular mortality (HR 0.41 [0.24; 0.71], p = 0.014), in patients with any degree of left ventricular function (29). These findings are in line with those for SGLT2 inhibitors when used to treat heart failure.

For patients with atrial fibrillation or flutter, oral anticoagulation is recommended regardless of the CHA₂DS₂-VA score, because of the high risk of embolism (ESC class I, level B evidence) (17). Rate control alone is often not a feasible treatment because of restrictive hemodynamics, and so rhythm control, preferably with amiodarone, is often considered on an individual basis, (18, 30). Catheter ablation can restore sinus rhythm, but its success rate is limited, and repeat interventions are not uncommon.

Specific treatment approaches

Indications

Specific treatment is indicated for confirmed ATTR-CM and whenever a clinically relevant benefit can be expected on the basis of the symptom stage, functional reserve, and overall prognosis. The indication is particularly compelling for patients with early-stage disease (NYHA I–II) (31, 32). In patients with NYHA class IV, significant comorbidity, or limited life expectancy, the potential individual clinical benefit should be carefully weighed within the framework of a rational, patient-centered treatment strategy. For ATTR-CM with a mixed phenotype, a gene-silencing drug may be appropriate, as efficacy data are available for these drugs against both types of manifestation—e.g., for vutrisiran (33). Since direct comparative studies between the available drugs are lacking, drugs cannot be ranked for the treatment of each clinical subtype. If there is clinical progression despite treatment, the treatment strategy should be reviewed and adjusted, if necessary, once alternative causes have been ruled out.

Treatment strategies

Current evidence is summarized in the Table (for further details, see eTable 2). There are two disease-modifying treatment strategies for ATTR amyloidosis: TTR stabilization and lowering hepatic TTR synthesis by gene silencing. Early treatment leads to better outcomes (3).

Table

The table includes all published randomized controlled trials of approved drugs. ATTR-CM, transthyretin amyloidosis with cardiomyopathy; bid, twice daily; HR, hazard ratio; n, group size; p, p-value; p.o., per os; pts. patients; q12wk, every 12 weeks; RR, relative risk; sc, subcutaneous(ly); ADE, adverse drug event; vs., versus; win ratio, hierarchical measure of comparison for combined endpoints, where values greater than 1 indicate a benefit of the treatment.

eTable

Warning signs of cardiac amyloidosis

TTR stabilizers

Tafamidis, a selective TTR stabilizer, binds to the thyroxine-binding site and prevents the tetramer from splitting into its monomeric constituents (31). Tafamidis has been approved for the treatment of ATTR-CM in patients with hereditary or wild-type ATTR who are in NYHA class I or II (ESC Guideline (2021), class I recommendation). It is recommended both to control symptoms and to lessen cardiovascular hospitalizations and mortality (34) (Tabelle). The dosage is 61 mg po qd (31).

Acoramidis was approved in the EU for the treatment ATTR-CM in February 2025. It stabilizes transthyretin by interacting via hydrogen bonds with the adjacent serine in the thyroxine binding site (32). In the ATTRibute-CM trial, nearly complete stabilization of transthyretin (>90% ex vivo) was seen within four weeks (35). At 30 months, there was a significant benefit compared to placebo with regard to the hierarchical 4-component endpoint (death, cardiovascular hospitalization, NT-proBNP, and 6-minute walk distance) (35) (Table). There was also a reduction in the composite endpoint of all-cause mortality or first cardiovascular hospitalization, beginning three months after the initiation of treatment and becoming larger over time (36). Moreover, acoramidis halved the annual rate of cardiovascular hospitalization and improved both health-related quality of life and physical endurance, as measured by the 6-minute walk distance (35). The recommended dose is 712 mg po bid. Gastrointestinal manifestations and gout were more common at lower doses (32).

RNA silencing

An alternative disease-modifying strategy is RNA interference, which lowers hepatic TTR synthesis and, in turn, diminishes the deposition of TTR in the tissues. Both vutrisiran and patisiran have been approved for the treatment of ATTR-related polyneuropathy; vutrisiran is also approved for ATTR-CM with or without polyneuropathy (9, 33). In the randomized, double-blind, phase 3 HELIOS-B trial (level Ib evidence), vutrisiran was evaluated in patients with ATTR-CM over a period of 36 months. The analysis was prespecified in the overall population with and without tafamidis therapy at baseline, as well as in a monotherapy population (37). Vutrisiran yielded a benefit In both populations with respect to the primary endpoint, a composite of all-cause mortality and recurrent cardiovascular events (37) (Table). Moreover, the functional state and health-related quality of life of the patients who received vutrisiran declined to a lesser extent, and their NYHA class more frequently remained constant or improved. These became apparent after ca. six months of treatment (37). In the monotherapy population, vutrisiran significantly lowered all-cause mortality in the extended 42-month follow-up period (37). No new information relevant to patient safety emerged, and the treated patients’ adverse events mostly reflected the underlying disease (37). The dosage of vutrisiran is 25 mg sc every three months.

The serum TTR level and its prognostic role

The findings of the meta-analysis of Terentes-Printzios et al. imply that the serum concentration of TTR can be considered a prognostic marker (38): across all populations, a 10 mg/dL fall in TTR concentration was found to be associated with a 73% rise in the risk of death from any cause (HR 1.73 [1.55; 1.91], p < 0.001). As TTR is considered a negative acute-phase protein, low levels may also nonspecifically indicate systemic inflammation or malnutrition. At the same time, there is ongoing discussion as to whether an inflammatory/oxidative environment might impair tetramer stability and promote amyloidogenic processes. For the purpose of treatment, the interpretation of TTR levels should be based on drug class: they should rise when stabilizers are used (e.g., with acoramidis, each increase of +5 mg/dL was associated with a −31.6% reduction in deaths of any cause). Low TTR levels despite the use of stabilizers may signify non-response. With RNA silencers, on the other hand, a marked lowering of the TTR level (~80–90%) is the goal and is associated with improvements in NT-proBNP and troponin levels, remodeling, and function (38).

Follow-up

The follow-up care for ATTR-CM is intended to enable the early detection of disease progression and complications and corresponding adjustments of supportive treatment and rhythm management. The consensus recommendation for follow-up care is that it should focus on functional status/activities of daily living, decompensation and hospitalization, and evidence of volume overload (9). A multimodal assessment of disease progression with biomarkers and noninvasive imaging is recommended as well (8). The course of the disease must be assessed in a broad overview of its manifestations over time, as there are currently no validated progression markers for ATTR amyloidosis (9). In practice, clinical and laboratory follow-up is conducted every 3 to 6 months, and the annual cardiological follow-up includes resting and long-term EKG (to detect arrhythmias and conduction disturbances) and echocardiography, including strain analysis. Cardiac MRI can be used to answer specific diagnostic questions, or if progression is suspected (8, 9). If ATTR-CM is confirmed, a neurological evaluation is indicated.

Conflict of interest statement

Ibrahim El-Battrawy has received compensation from Alnylam for an educational event (round table) and reimbursement of travel expenses and meeting participation fees from Bayer.

Arash Haghikia has received compensation from Bayer, Pfizer, and Boehringer Ingelheim for educational events.

Tienush Rassaf is a co-founder of MyCor GmbH, which has developed a 3D ECG for the diagnosis of amyloidosis. He received financial support from Bayer for this work. He has received lecture honoraria from AstraZeneca, Bayer, Novartis, BMS, Berlin Chemie, Daiichi Sakyo, Boehringer Ingelheim, Novo Nordisk, Cardiac Dimensions, and Pfizer and reimbursement of travel expenses and/or meeting participation fees from the DGK and Bayer. He serves on the advisory boards of Cytokinetics, Bayer, and Alnylam, as well as those of the DGK and the DFG.

The remaining authors state that they have no conflict of interest.

Manuscript submitted on 26 October 2025, revised version accepted on 11 May 2026.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Ibrahim El-Battrawy

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