Transthyretin amyloid cardiomyopathy: Literature review and red‐flag symptom clusters for each cardiology specialty

Abstract

Wild‐type transthyretin amyloid cardiomyopathy (ATTRwt‐CM) is a progressive and infiltrative cardiac disorder that may cause fatal consequences if left untreated. The estimated survival time from diagnosis is approximately 3–6 years. Because of the non‐specificity of initial symptom manifestation and insufficient awareness among treating physicians, approximately one‐third of patients with ATTRwt‐CM are initially misdiagnosed with other cardiac diseases. Although heart failure (HF) is the most common initial manifestation of ATTRwt‐CM, observed in nearly 70% of affected patients, patients may also present with other cardiologic symptoms, such as atrial fibrillation (AF) and aortic stenosis (AS). This non‐specific and diverse nature of the initial ATTRwt‐CM presentation indicates that various cardiology subspecialties are involved in patient diagnosis and management. Standard guideline‐directed pharmacological treatment for HF is not recommended for patients with ATTRwt‐CM because of its limited effectiveness. However, no established algorithms are available regarding HF management in this patient population. This literature review provides an overview of the red flags for ATTRwt‐CM and research findings regarding HF management in this patient population. In addition to commonly recognized red flags for ATTRwt‐CM (e.g., HF, AF and severe AS), published literature identified potential red flags such as coronary microvascular dysfunction. For HF management in patients with ATTRwt‐CM, the use of mineralocorticoid receptor antagonists (MRAs) was reported as a well‐tolerated option associated with a low discontinuation rate and reduced mortality. Although there is no concrete evidence for recommendations against sodium‐glucose cotransporter 2 inhibitor (SGLT2i) administration, research supporting its use is limited to small‐scale studies. Robust evidence is lacking for AF ablation, implantable cardioverter‐defibrillators and cardiac resynchronization therapy. Based on the published findings and our clinical experience as Japanese ATTRwt‐CM experts, red‐flag symptom clusters for each cardiology specialty (HF, arrhythmia and ischaemia/structural heart disease) and a treatment scheme for HF management are presented. As this research area remains at an exploratory stage, our observations would require further discussion among experts worldwide.

Introduction

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is a progressive, infiltrative cardiomyopathy (CM) manifesting as a range of cardiac symptoms, including conduction disturbance, arrhythmia and progressive heart failure (HF).^1–6 If left untreated, the disease has a poor prognosis, with patients advancing to intractable HF and death.^3,5 The true prevalence of ATTRwt-CM is uncertain, as it is frequently underrecognized.⁷ However, recent advances in diagnostic imaging modalities and algorithms have increased the frequency of diagnoses and positively changed the medical landscape of ATTRwt-CM.^1,8–11 Tafamidis meglumine, currently the only approved drug for ATTRwt-CM treatment,^12–15 is an important advancement in its treatment¹⁶ that requires a precise and early disease diagnosis to gain maximal clinical benefit. Moreover, ATTRwt-CM is often accompanied by non-specific findings such as HF with preserved ejection fraction (HFpEF), which indicates that this disease is often overlooked or misdiagnosed as other cardiovascular diseases. Such misdiagnoses include hypertensive heart disease (HHD) and hypertrophic CM (HCM), leading to delayed diagnosis and potentially avoidable disease progression.¹⁷ To address this problem, clinicians should identify the diagnostic clues or red flags, that is, signs and symptoms crucial for accurate and early ATTRwt-CM diagnosis. Published evidence has assisted many HF specialists in investigating red flags for ATTRwt-CM in daily clinical practice.^3,11,18,19 However, ATTRwt-CM is highly likely to be encountered by other cardiology specialists, such as arrhythmia and ischaemia/structural heart disease (SHD) specialists, necessitating more precise red flags for these individual specialties.

Achieving both disease progression control and HF management is essential for improving patient outcomes. Tafamidis is effective in suppressing the new deposition of amyloid fibrils and delaying disease progression.⁴ Conventional HF treatments that have proven effectiveness in treating HF with reduced ejection fraction (EF) are less effective in patients with cardiac amyloidosis (CA).^20,21 Thus, worldwide expert recommendations and consensus documents do not advocate the use of standard guideline-directed pharmacological treatment for HF in patients with ATTRwt-CM.^7,11,22 Although the guidelines for CA issued by the Japanese Circulation Society (JCS) provide recommendations for HF management, no established treatment algorithms are available.²

This literature review discusses the red flags for ATTRwt-CM and the evidence regarding HF management in this patient population. We also explore whether red-flag symptom clusters for each cardiology specialty (HF, arrhythmia and ischaemia/SHD) and a treatment scheme for HF management can be established. These discussions are based on a medical advisory board meeting held on 28 August 2022 that was joined by a group of Japanese ATTRwt-CM experts. The findings discussed in this work are in the exploratory stage and would require further discussion among experts worldwide. Confirmation through large-scale studies or systematic review approaches is warranted.

Why are red flags important for ATTRwt-CM?

The progressive and fatal nature of ATTRwt-CM necessitates its early diagnosis and timely treatment to determine the patient's subsequent prognosis.³ If left untreated, the disease may cause fatal consequences, with an estimated survival time of 3–6.25 years from the time of diagnosis.^3,5,23 ATTRwt-CM is a truly overlooked disease. Autopsy data have shown that among adults aged ≥85 years, 25% had significant transthyretin (TTR) amyloid deposits in the myocardium.²⁴ However, data from the Mayo Clinic in the United States indicate that the ages of 360 patients diagnosed with ATTRwt-CM before death ranged from 47 to 94 years,²⁵ suggesting that the target patient population should not be limited to individuals aged ≥80 years.

A low awareness of ATTRwt-CM frequently leads to patients being misdiagnosed with other cardiac disorders or experiencing delayed diagnoses.^3,11 Patients often consult multiple physicians before receiving an accurate diagnosis,¹¹ and 35% of patients with ATTRwt-CM are misdiagnosed with other cardiac diseases, such as HHD and HCM.¹⁷ Indeed, 5.2%–23.5% of patients with ATTRwt-CM have been previously misdiagnosed with HCM,^17,26 and the latest European Society of Cardiology (ESC) guidelines on HCM have acknowledged the role of bone tracer scintigraphy in the differential diagnosis of ATTRwt-CM.²⁷ Furthermore, patients with ATTRwt-CM present with diverse cardiac findings, including electrocardiogram (ECG) and echocardiogram abnormalities, atrial fibrillation (AF), aortic stenosis (AS) and conduction disturbance.³ These findings suggest that patients with ATTRwt-CM are managed by a variety of cardiology subspecialties, highlighting the need to increase awareness of specific red flags for ATTRwt-CM.

Red flags commonly identified in the literature

Red-flag symptom clusters and diagnostic algorithms for ATTRwt-CM have been discussed in existing publications worldwide.^{3,18,19,28–30} This section provides an overview of the red flags commonly identified in the literature.

Patient background

ATTRwt-CM is more common in men (male-to-female ratio: 25–50:1), typically aged >60 years.⁵ A high level of ATTRwt-CM suspicion exists for cardiac hypertrophy in men with HF aged >60 years² and women with HF aged >70 years.²⁸

Medical history

Despite the heterogeneity in clinical manifestations, HF remains the predominant profile leading to ATTRwt-CM diagnosis, accounting for 68% of the diagnosed cases.¹⁷ Previous research has revealed that 13% of elderly patients with HFpEF admitted to a hospital were subsequently diagnosed with ATTRwt-CM,³¹ indicating the importance of HFpEF as an early disease indicator. Carpal tunnel syndrome (CTS) is also widely recognized as an early disease marker of ATTRwt-CM.^32–37 According to an examination of 700 Japanese patients who underwent carpal tunnel release, 261 (37%) of them had amyloid deposition.³⁸ Furthermore, among 120 patients who underwent cardiac screening, 6 (5%) had concomitant CA.³⁸ ATTRwt-CM may be suspected in elderly patients with a history of CTS or orthopaedic surgery for CTS, lumbar spinal stenosis or biceps tendon rupture,^32–38 as these conditions may be caused by amyloid fibril deposition in the ligaments and tendons.^3,34 Biceps tendon ruptures are more often observed in patients with ATTRwt-CM than in those without ATTRwt-CM,³⁵ which is also a common initial symptom of ATTRwt-CM.³

Electrocardiographic and echocardiographic findings

Conduction disturbance and low voltage are commonly reported as ECG findings observed among patients with ATTRwt-CM.³ In addition, various echocardiographic findings are suggestive of infiltrative disease and trigger ATTRwt-CM suspicion.

Increased left ventricular (LV) wall thickness resulting from amyloid fibril deposition is the most prominent characteristic of ATTRwt-CM,^28,31 which is often misdiagnosed as HHD, concentric hypertrophy from AS, HCM or other infiltrative CMs such as Fabry disease.¹¹ Therefore, particular attention needs to be paid to patients with unexplained left ventricular hypertrophy (LVH) or LVH without apparent underlying causes. An LV wall thickness of ≥14 mm is generally recognized as a red flag^28,31 but may not be applicable to Asian patients because of the lower body mass index range for the definition of obesity³⁹ and the smaller LV diastolic diameter in the Japanese population.³ For Asian patients, an LV wall thickness of ≥12 mm is suggested as a sign of suspecting LVH,^3,22,31 but further research is warranted.

Additional echocardiographic findings can trigger a suspected ATTRwt-CM diagnosis. A large, prospective, clinical follow-up programme assessed the prognosis of 1240 patients with ATTRwt-CM using echocardiographic parameters. These patients had significantly lower indices of LV function, and several parameters were independently associated with mortality, such as E/e′ and stroke volume (all P < 0.05).⁴⁰ Right ventricular (RV) involvement is also common in patients with ATTRwt-CM.^2,3,6,11 Arvidsson et al. demonstrated a reduction in RV systolic function with a concurrent increase in LV wall thickness in 24% of patients with ATTRwt-CM. The RV function in patients with ATTRwt-CM was attributable to LV systolic or diastolic dysfunction and increased LV wall thickness.⁴¹ The same group also detected an RV apical sparing pattern in patients with ATTRwt-CM,⁴¹ similar to that previously described for LV in these patients.^22,28 Another multicentre cohort study involving 1187 patients with CA indicates that a combination of relative wall thickness, E/e′, longitudinal strain, tricuspid annular plane systolic excursion and systolic apex-to-base ratio can help detect CA in patients with increased wall thickness.⁴²

Combinations of ECG and echocardiographic findings further improve CA detection. Paradoxical LVH, defined as a combination of LV wall thickness of ≥12 mm, SV1 + RV5 < 3.5 mV and lack of secondary ST-T abnormalities, serves as an independent factor for CA detection in patients with LVH and can detect CA with a high sensitivity (80%) and specificity (84%).⁴³ Moreover, a combination of ECG low voltage and interventricular septal thickness of >1.98 cm can establish CA diagnosis with a high sensitivity (72%) and specificity (91%).⁴⁴

Cardiac magnetic resonance and computed tomography

An increase in myocardial extracellular volume (ECV) is commonly observed in patients with CA and is generally detectable using cardiac magnetic resonance (CMR) imaging.⁴⁵ Recently, computed tomography (CT) has been employed for measuring myocardial ECV in patients with CA.^46,47 According to a single-centre study conducted in Japan, ATTRwt-CM was diagnosed in 6 of 16 patients who were referred for AF ablation and had a high (>35%) myocardial ECV based on CT measurement.⁴⁸ Patients with severe AS undergoing transcatheter aortic valve implantation (TAVI) or replacement (TAVR) are typically offered contrast CT as part of routine assessments, which can reliably detect an increased myocardial ECV.⁴⁹ The addition of myocardial ECV analysis using CT to TAVI/TAVR planning in patients with severe AS also appears clinically practical for the non-invasive identification of occult ATTRwt-CM.⁵⁰

Laboratory findings

Elevations in N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT) or high-sensitivity troponin I (hs-TnI) levels are common in patients with ATTRwt-CM.³ Persistent elevation in the cardiac troponin level is frequently observed, particularly in patients with AS, and suggests ongoing subclinical myocardial damage in patients with ATTRwt-CM.^51–53 For hs-TnT, a cut-off level of 0.0315 ng/mL in the serum can help differentiate patients with ATTRwt-CM from control adults, with a sensitivity of 83% and a specificity of 76%.⁵¹ In contrast, lower levels of NT-proBNP (<180 ng/L) and hs-TnT (<14 ng/L) can exclude CA even in patients referred for suspected diagnosis.⁵⁴

Poor treatment response

Patients who remain refractory to standard guideline-directed treatment for HF management should raise ATTRwt-CM suspicion. Angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), angiotensin receptor–neprilysin inhibitors (ARNIs) and beta-blockers are not well tolerated by patients with CA because of adverse reactions such as hypotension.⁵⁵ Patients with persistently high brain natriuretic peptide (BNP) levels despite beta-blocker and ACEi treatment are highly suspected of having ATTRwt-CM.^5,55

Arrhythmia and recurrent arrhythmia

AF is the most common arrhythmia encountered in patients with ATTRwt-CM, observed in almost half of the patients during diagnosis.^17,23 The reported prevalence of arrhythmia is highly variable, ranging from 15% to 70% across all CA subtypes.^11,56,57

Arrhythmia recurrence in patients with ATTRwt-CM is common following ablation.⁵⁸ In a study evaluating 24 patients with ATTRwt-CM who underwent AF ablation, 58% developed recurrent arrhythmia during a mean follow-up period of 39 months.⁵⁷ In addition, the incidence rate of recurrent arrhythmia was significantly higher for patients with stage III ATTRwt-CM (based on the scoring system proposed by Gillmore et al.⁵⁹) than for those with stage I or II ATTRwt-CM (90% vs. 36%; P = 0.005).⁵⁷ Another single-centre study conducted in Japan reported that among 57 patients who were referred for AF ablation and underwent CT for myocardial ECV measurement, 6 were eventually diagnosed with ATTRwt-CM.⁴⁸

Conduction disturbance requiring pacemaker implantation

Conduction disturbance requiring pacemaker implantation is another red flag to consider. Although the sample size was small, a single-centre study in the United Kingdom reported that ATTRwt-CM was diagnosed in 3 of 39 (7.7%) patients aged 70–85 years who had idiopathic high-degree atrioventricular block requiring pacemaker implantation.⁶⁰ In a retrospective, observational cohort study of 78 patients with ATTRwt-CM who used cardiac implantable electronic devices, an RV pacing burden of >40% resulted in adverse structural and clinical consequences, including higher New York Heart Association (NYHA) functional classes, LVEF worsening and increased mitral regurgitation severity.⁶¹ Another retrospective cohort study of 369 patients diagnosed with ATTRwt-CM demonstrated that 11% developed a high-grade atrioventricular block requiring a permanent pacemaker and an additional 7% developed sinus node dysfunction during a mean follow-up of 28 months.⁶²

Pseudo-infarct pattern and coronary microvascular dysfunction

Abnormal Q waves and poor R wave progression in a patient without obstructive coronary artery disease (CAD), called a pseudo-infarct pattern, is a common finding observed in 18%–71% of patients with ATTRwt-CM.² However, the absence of a pseudo-infarct pattern does not exclude an ATTRwt-CM diagnosis.

Recent research findings indicate coronary microvascular dysfunction (CMD) as another clinical presentation of ATTRwt-CM.⁶³ CMD is associated with common characteristics of CA, such as high LV mass, low mitral annular relaxation velocities, impaired longitudinal myocardial strain and elevated left atrial pressure.⁶³ Amyloid fibril accumulation in the cardiac interstitium and perivascular areas can increase resistance in the coronary microvasculature and LV filling pressures, resulting in greater susceptibility to ischaemia and latent impairment of LV systolic function.⁶³ According to a Japanese study that assessed coronary flow reserve and hs-TnT levels in 58 patients with HF without CAD, hs-TnT levels were significantly higher among those with CMD, and all 4 patients with CA presented with CMD.⁶⁴ A single-centre, prospective, observational study of 61 patients with CTS and 36 healthy controls reported a statistically significant increase in the carotid intimal-media thickness in those with CTS and concomitant amyloidosis.⁶⁵ However, a significant change in other parameters for arterial abnormalities, such as coronary flow velocity reserve and flow-mediated vasodilatation, was observed even in patients without concomitant amyloidosis.⁶⁵ CA is recognized as a phenotype of CMD in the Japanese guidelines for vasospastic angina and CMD.⁶⁶ However, further investigation is warranted as robust evidence remains limited.⁶⁷

Severe AS requiring TAVI or TAVR

Severe AS requiring TAVI or TAVR,⁶⁸ along with a poor treatment response (e.g., HF progression after TAVI or TAVR),⁶⁹ also triggers ATTRwt-CM suspicion. ATTRwt-CM is observed in approximately 10% of elderly patients with severe AS,⁷⁰ and 16% of such patients have a low-flow, low-pressure gradient pattern.^68,71 Factors such as LVEF <50%, reduction (at least −10%) in global longitudinal strain, a restrictive pattern (grade 3 diastolic dysfunction), moderate-to-severe low-flow state and low-gradient AS are associated with poor prognosis in patients with CA undergoing aortic valve replacement.⁷² Patients with severe AS and concomitant ATTRwt-CM often present with other red flags, including advanced age, male sex, prior carpal tunnel surgery, ECG findings and echocardiographic changes.⁷⁰ Although CA diagnosis in the presence of AS poses a challenge because of overlapping clinical features,⁷³ the combination of severe AS and other red flags warrants further clinical evaluation for early and accurate ATTRwt-CM diagnosis.⁷⁰

Can red-flag symptom clusters be established for each cardiology subspeciality? Japanese experts' perspective

The red flags identified in the literature can be summarized as symptom clusters common across subspecialties and those commonly observed at HF, arrhythmia and ischaemia specialties (Figure 1). This summary indicates that further research is warranted to discuss red-flag symptom clusters for arrhythmia and ischaemia specialists. Moreover, a suspected diagnosis of ATTRwt-CM needs to be followed by subsequent tests to establish a formal diagnosis. Bone tracer scintigraphy, biopsy and amyloid typing can be offered based on the regional clinical practice and healthcare reimbursement systems.^1,3

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Treatment optimization and management of HF in patients diagnosed with ATTRwt-CM

Once the ATTRwt-CM diagnosis is established, the treatment regimen for the patient needs to be reviewed and modified to achieve both disease progression control and HF management for improved patient outcomes.

Progression control with tafamidis: Published findings

Tafamidis, a TTR tetramer stabilizer, is currently the only approved drug for ATTRwt-CM.^12–15 Clinical practice guidelines for HF recommend tafamidis for patients with ATTRwt-CM.^74,75 The pivotal trial ATTR-ACT (Tafamidis in Transthyretin Amyloidosis Cardiomyopathy Clinical Trial) demonstrated that tafamidis was associated with lower all-cause mortality [29.5% vs. 42.9%; hazard ratio, 0.70; 95% confidence interval (CI), 0.51–0.96] and a lower rate of cardiovascular-related hospitalizations (0.48 vs. 0.70 per year; 95% CI, 0.56–0.81; relative risk ratio, 0.68) than placebo over a 30-month treatment period.⁴ The number needed to treat was 7.5 (preventing 1 death over 2.5 years) for all-cause mortality and 4 (preventing 1 hospitalization per year) for cardiovascular-related hospitalizations.⁷⁶ The incidence rates and types of adverse events were not notably different between the tafamidis and placebo groups.⁴ Patients who completed ATTR-ACT were eligible for participation in the long-term extension study, in which those who had been treated with placebo in ATTR-ACT were initiated on tafamidis treatment. Consequently, all-cause mortality was significantly lower in patients who continued tafamidis than in those who switched from placebo to tafamidis (44.9% vs. 62.7%; median follow-up, 58.5 vs. 57.1 months; hazard ratio, 0.59; 95% CI, 0.44–0.79; P < 0.001).⁷⁷ No new safety concerns were identified in the long-term extension study.⁷⁷

Recent studies in Japan have shown the effectiveness of tafamidis in patients with ATTRwt-CM in real-world clinical settings.^16,78,79 According to a single-centre retrospective study that involved 125 patients treated with tafamidis and 55 untreated patients, patients receiving tafamidis showed a significant reduction in all-cause mortality, HF-related hospitalization and hs-TnT levels versus untreated patients.¹⁶ Another single-centre retrospective study that involved 38 patients treated with tafamidis and 44 untreated patients showed a rate of cardiovascular hospitalizations of 0.19 per year and a 1-year survival rate of 92% in the tafamidis treatment group, without significant deterioration in cardiac biomarkers or parameters.⁷⁸ No adverse events leading to tafamidis discontinuation were reported.⁷⁸ Echocardiographic examinations of 41 Japanese patients with ATTR-CM treated with tafamidis found no significant changes in echocardiographic parameters during a 16-month follow-up, and the effectiveness of tafamidis extended to patients with advanced cardiac diseases and those with advanced age.⁷⁹

Can standard guideline-directed pharmacological treatment for HF be continued after ATTRwt-CM diagnosis?

Beta-blockers, ACEis and ARBs are not recommended for patients with ATTRwt-CM^7,11,22 and are not widely prescribed in this patient population.⁸⁰ A prescription pattern analysis of 2371 patients with ATTR-CM revealed that beta-blockers were prescribed to only 55.4% of them, and the proportion of patients treated with ACEis or ARBs was limited to 57.4%.⁸⁰ In patients with ATTRwt-CM, beta-blockers may be harmful as they further reduce the cardiac output.²⁰ For patients previously treated with beta-blockers for tachycardic AF, guidelines recommend the discontinuation of this treatment, especially when symptomatic hypotension and bradyarrhythmia are present.^7,20,22,55 When heart rate control is necessary, the lowest effective dose is recommended.²⁰ The safety of beta-blocker administration to patients with ATTRwt-CM has been reported in small-scale Italian and Spanish studies.^81,82 Hypotension also occurs in patients with ATTRwt-CM treated with ARNIs.⁵⁵

The aforementioned prescription pattern analysis suggests that a mineralocorticoid receptor antagonist (MRA) is a well-tolerated option for ATTRwt-CM.⁸⁰ In this study, the prescription rate for MRAs was limited to 39.0% at baseline, but its discontinuation rate during a median follow-up of 27.8 months was substantially low (7.5%) compared with that for beta-blockers (21.7%) or ACEis or ARBs (32.9%).⁸⁰ Moreover, treatment with MRAs was independently associated with a reduced risk of mortality.⁸⁰

There is no established evidence leading to recommendations against the use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) in patients with ATTRwt-CM. Two small studies support the efficacy of SGLT2is in patients with TTR amyloid cardiomyopathy, including ATTRwt-CM.^83,84 A retrospective analysis of the Bern Amyloidosis Registry assessed the short-term tolerability and effects of dapagliflozin and measured NT-proBNP levels in patients treated with tafamidis.⁸³ Seventeen patients treated with tafamidis who subsequently initiated dapagliflozin were compared with a reference cohort of 40 patients treated with tafamidis without SGLT2i. The onset of clinical adverse events, including death, worsening HF episodes and arrhythmias, was assessed until 3 months of follow-up. At the 3-month follow-up, no HF-associated deaths, worsening HF episodes or new-onset arrhythmias were observed, and a numerical decrease in NT-proBNP levels was observed in 13/17 (76.5%) patients treated with both tafamidis and dapagliflozin and 27/40 (67.5%) patients treated with tafamidis without SGLT2i; overall, the patients remained stable, and dapagliflozin was well tolerated.⁸³ Another real-world case series described the clinical course of 15 patients with TTR amyloid cardiomyopathy and diabetes treated with SGLT2i [median age, 80 years; 14 (93%) men; mean follow-up, 8 months], including 13 with ATTRwt-CM.⁸⁴ Three patients showed improvement in HF symptoms without modifying the furosemide dose (NYHA class III to II in two patients; NYHA class II to I in one patient), while two showed worsening from NYHA class I to II. Patients who continued SGLT2i showed a non-significant decrease in the estimated glomerular filtration rate (eGFR) from 43 to 34 mL/min (P = 0.142), indicating that SGLT2i treatment leads to a short-term decline in patients' renal function; however, this decline generally becomes slower in the long term.⁸⁴

What kind of clinical events may occur after the initiation of HF treatment, and what treatment changes are recommended in the literature?

Despite treatment with tafamidis and HF medications, patients with ATTRwt-CM occasionally develop complications such as decreased renal function, reduced EF, AF onset and HF exacerbation, which occasionally lead to a poor prognosis.^2,59,85 Researchers at the National Amyloidosis Centre of the United Kingdom reported that albuminuria was observed in 563/1181 (47.7%) patients with TTR amyloid cardiomyopathy, with the majority [499 (88.6%)] having microalbuminuria.⁸⁶ A staging system that combines NT-proBNP and eGFR enables effective patient stratification based on predicted survival,^59,85 which illustrates the utility of HF exacerbation and renal function decline as survival indicators for ATTRwt-CM. In a single-centre retrospective cohort study of 382 patients with TTR cardiomyopathy (including 271 with ATTRwt-CM), 265 (69%) had AF, with 177 (67%) diagnosed with AF after TTR cardiomyopathy diagnosis (median time to diagnosis: 15 months).⁸⁷ These clinical events often require treatment changes. The authors' observations are summarized in Table 1.

Table 1 Treatment strategy according to the occurrence of clinical events after ATTRwt-CM diagnosis: Japanese experts' perspective.

Clinical event	Treatment strategy
Decreased renal function	SGLT2i can be continued83,84 The dose of loop diuretics may be reduced, and tolvaptan may be added88
Decreased EF	MRA (spironolactone) is an alternative diuretic option for individuals who have a poor response to loop diuretics, if used by carefully monitoring patients' renal function and potassium levels The treatment discontinuation rate of MRAs is low (7.5% during a median follow-up of 27.8 months)80
Onset of AF	AF ablation is associated with reduced mortality and is most effective when performed earlier during the disease process57 The risk of thromboembolism needs to be managed with anticoagulants55,58 If a patient remains symptomatic, amiodarone without beta-blockers may be considered56
Exacerbation of HF	When HF reaches NYHA class III, the dose of ARB or ACEi may be reduced, as necessary Inotropes may be used in the hospital setting, starting with a small dose of pimobendan An addition or dose increase of diuretics may be considered for patients with stable renal function

Small studies have suggested that SGLT2i treatment is a well-tolerated option for HF management in patients with ATTRwt-CM.^83,84 In patients experiencing decreased renal function, reducing the dose of loop diuretics and adding tolvaptan can improve renal function, as demonstrated in patients with congestive HF.⁸⁸ Increasing the diuretic dose can lead to renal function worsening, as shown in patients with HF with reduced EF.⁸⁹ The low discontinuation rate of MRAs (7.5%, during a median follow-up of 27.8 months) substantiates this agent as a well-tolerated option for patients with ATTRwt-CM.⁸⁰ Therefore, MRAs can be an alternative diuretic option for patients developing a reduction in EF who respond poorly to loop diuretics, if used by carefully monitoring patients' renal function and potassium levels.

AF commonly develops in patients with ATTRwt-CM and is more prevalent in those with advanced disease stages.⁸⁷ AF ablation is associated with reduced mortality and is most effective when performed earlier during the disease process.^57,87 A retrospective observational study that included 24 patients with ATTRwt-CM undergoing ablation and 48 with ATTRwt-CM receiving medical management reported that 42% of ablation patients remained free of recurrent arrhythmia during an average follow-up period of 39 months.⁵⁷ The mortality rate was lower in the ablation group (29%) than in the medical management group (75%), and ablation was associated with a significant reduction in hospitalization frequency for HF/arrhythmia.⁵⁷ Nevertheless, the timing and procedures for AF ablation have not been standardized in ATTRwt-CM treatment, which warrants further large-scale studies. Intracardiac thromboembolism is commonly observed in patients with CA (33%, with 40% having multiple thrombi).⁵⁸ Therefore, anticoagulants are generally prescribed to patients with ATTRwt-CM and AF regardless of the CHA₂DS₂-VASc risk score, unless there are contraindications.^55,58 There is limited evidence to recommend direct oral anticoagulants over warfarin for AF management in patients with ATTRwt-CM.¹¹ Treatment with beta-blockers, calcium-channel blockers or digoxin poses risks in the management of atrial arrhythmias, and antiarrhythmics are occasionally prescribed for patients with CA; however, the benefit of rhythm control with antiarrhythmics is limited and does not always contribute to improved survival in this population.⁵⁶ Amiodarone is generally well tolerated in patients with CA,⁵⁶ but bradycardia may occur.⁹⁰

7HF worsening in patients with ATTRwt-CM requires a considerable change in the treatment strategy. Dobutamine infusion is often used in inpatient settings, but weaning from the drug is often a challenge.⁹¹ Pimobendan may be an effective option to manage HF in ATTRwt-CM while enabling the termination of dobutamine infusion, although the current evidence is limited to a case series.⁹¹ Two case series studies published in 2023 have suggested that the ARNI sacubitril-valsartan was well tolerated by patients with ATTRwt-CM with reduced EF.^92,93 However, its effectiveness and safety should be further investigated in large-scale, controlled settings.

Patients with ATTRwt-CM may develop bradyarrhythmia, but research on its management is limited. Many clinical questions remain unaddressed, including the effectiveness of cardiac resynchronization therapy (CRT) in patients requiring ventricular pacing.

Are implantable electronic devices effective?

Published literature reports that 8.9% of patients with CA underwent pacemaker implantation within 3 years of diagnosis.⁹⁴ The effectiveness of implantable cardioverter-defibrillators (ICDs) and CRT/CRT defibrillators (CRT-Ds) has been evaluated (Table 2); however, evidence remains insufficient to fully support their use in patients with ATTRwt-CM.

Table 2 Published findings regarding the use of implantable electronic devices in patients with ATTRwt-CM.

Implantable electronic device	Published findings
ICD	ICDs may not provide significant survival benefits in terms of reducing sudden cardiac death95 Prophylactic ICD implantation remains controversial96,97
CRT/CRT-D	In patients who met the guideline criteria for device implantation, CRT was associated with improved survival and improvements in HF symptoms98 The clinical utility in patients with ATTRwt-CM remains controversial

ICDs do not appear to improve survival in patients with ATTRwt-CM and do not provide significant benefits in terms of reducing sudden cardiac death.⁹⁵ A small study investigating the effectiveness of ICDs in patients with CA found no significant difference in mortality between patients with and without ICD implantation (39% vs. 46%, P = 0.59).⁹⁵ Indeed, prophylactic ICD implantation remains controversial in treating patients with ATTRwt-CM.^96,97

Currently, the utility of CRT/CRT-Ds in patients with ATTRwt-CM remains clinically controversial, and CRT implantation is rarely applied in this patient population.⁹⁸ A single-centre retrospective study has suggested that CRT was associated with improved survival and improvements in HF symptoms in patients with ATTRwt-CM meeting the guideline criteria for device implantation.⁹⁸ Further data on the effectiveness and safety of CRT/CRT-Ds should be gathered.

Can a treatment scheme for ATTRwt-CM be established? Japanese experts' perspective

Published findings indicate that decisions to continue or discontinue conventional HF medications in patients with ATTRwt-CM need to be made based on the timing of diagnosis and clinical symptoms observed. A treatment scheme developed based on the authors' clinical experience is presented in Figure 2. In addition to the ATTRwt-CM diagnosis, tachycardia AF, EF decline (<40%–50%) and other clinical events that suggest HF worsening may trigger treatment changes. Further research is warranted to validate the feasibility of this scheme.

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Limitations

This review has some limitations. First, the red-flag symptom clusters divided by subspecialty and treatment scheme were framed mainly based on the clinical experience of Japanese cardiology experts, which limits the generalizability of the findings. Second, the findings supported only by small-scale observational studies or case series require confirmation through large-scale prospective studies and systematic reviews. Lastly, the exploratory nature of our work warrants further discussions among specialists worldwide to establish recommendations from academic societies.

Conclusions and future perspectives

In the current review, we summarized published findings regarding red flags for ATTRwt-CM and aimed to propose symptom clusters specific to cardiology subspecialties. We also attempted to discuss effective HF management strategies for ATTRwt-CM applicable in daily clinical practice. Identification of appropriate red flags can provide clues leading to suspected ATTRwt-CM diagnosis and appropriate intervention; however, the lack of established evidence for arrhythmia and ischaemia specialists remains an unmet need. Another unmet medical need is the lack of established criteria for continuing or discontinuing standard guideline-directed treatment for HF in patients with ATTRwt-CM. We believe that the current review will help cardiologists consider tailored treatment approaches for HF management in this patient population. Further large-scale studies are warranted to update expert recommendations and clinical guidelines.

Acknowledgements

Medical writing support was provided by Gwen Wiseman, BSc, and Mami Hirano, MSc, of Cactus Life Sciences (part of Cactus Communications) and was funded by Pfizer Japan Inc.

Conflict of interest statement

Yasuhiro Izumiya has received financial support for writing the present manuscript from Pfizer Japan; consulting fees from Pfizer Japan; and lecture fees from Pfizer Japan, Nippon Boehringer Ingelheim, Sanofi, Medtronic Japan, AstraZeneca, Toa Eiyo, Bayer Yakuhin, Takeda Pharmaceutical, Sumitomo Pharma, Janssen Pharmaceutical, Otsuka Pharmaceutical, Kowa, Novartis Pharma, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Viatris, Nippon Shinyaku, Kyowa Kirin and Alnylam Japan; and serves as an advisory board member for Pfizer Japan. Toru Kubo has received financial support for writing the present manuscript and lecture fees from Pfizer Japan and serves as an advisory board member for Pfizer Japan. Jin Endo has received funding support for writing the present manuscript from Pfizer Japan; grants from Pfizer Japan and Alnylam Japan; and lecture fees from Pfizer Japan and Janssen Pharmaceutical; and serves as an advisory board member for Pfizer Japan. Seiji Takashio has received funding support for the present manuscript from Pfizer Japan and speaker fees from Pfizer Japan and serves as an advisory board member for Pfizer Japan. Masatoshi Minamisawa has received funding support for writing the present manuscript from Pfizer Japan; funding from the Ministry of Health, Labour and Welfare grant-in-aid research (Grant No. 22K16099); consulting fees from Alexion Pharmaceuticals; and lecture fees from Pfizer Japan and Alnylam Japan; and serves as an advisory board member for Pfizer Japan. Jun Hamada, Tomonori Ishii, Hajime Abe and Hiroaki Konishi are full-time employees of Pfizer Japan. Kenichi Tsujita has received funding support for writing the present manuscript from Pfizer Japan; grants or scholarship from CSL Behring, Alexion Pharmaceuticals, AnGes, PPD-Shin Nippon Biomedical Laboratories, Sugi Bee Garden (International), Daiichi Sankyo, Bayer Yakuhin, Pfizer Japan, Bristol Myers Squibb, Mochida Pharmaceutical, EA Pharma, AMI, Abbott Medical, Nippon Boehringer Ingelheim, ITI, Ono Pharmaceutical, Otsuka Pharmaceutical and Takeda Pharmaceutical; and lecture fees from Abbott Medical, Amgen, AstraZeneca, Bayer Yakuhin, Daiichi Sankyo, Medtronic Japan, Kowa Pharmaceutical, Kyowa Kirin, Novartis Pharma, Otsuka Pharmaceutical, Pfizer Japan and Janssen Pharmaceutical; serves as an advisory board member for Pfizer Japan; and declares other relationships (affiliation with endowed departments) with Abbott Japan, Boston Scientific Japan, Fides-one, GM Medical, ITI, Kaneka Medix, Nipro Corporation, Terumo, Abbott Medical, Fukuda Denshi, Japan Lifeline and Medtronic Japan.

References

Tahara N, Lairez O, Endo J, Okada A, Ueda M, Ishii T, et al. ^99mTechnetium‐pyrophosphate scintigraphy: A practical guide for early diagnosis of transthyretin amyloid cardiomyopathy. ESC Heart Fail 2022;9:251‐262. doi:10.1002/ehf2.13693

Kitaoka H, Izumi C, Izumiya Y, Inomata T, Ueda M, Kubo T, et al. JCS 2020 guideline on diagnosis and treatment of cardiac amyloidosis. Circ J 2020;84:1610‐1671. doi:10.1253/circj.CJ‐20‐0110

Inomata T, Tahara N, Nakamura K, Endo J, Ueda M, Ishii T, et al. Diagnosis of wild‐type transthyretin amyloid cardiomyopathy in Japan: Red‐flag symptom clusters and diagnostic algorithm. ESC Heart Fail 2021;8:2647‐2659. doi:10.1002/ehf2.13473

Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington‐Cruz M, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med 2018;379:1007‐1016. doi:10.1056/NEJMoa1805689

Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012;126:1286‐1300. doi:10.1161/CIRCULATIONAHA.111.078915

Maurer MS, Bokhari S, Damy T, Dorbala S, Drachman BM, Fontana M, et al. Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis. Circ Heart Fail 2019;12: [eLocator: e006075]. doi:10.1161/CIRCHEARTFAILURE.119.006075

Kittleson MM, Maurer MS, Ambardekar AV, Bullock‐Palmer RP, Chang PP, Eisen HJ, et al. Cardiac amyloidosis: Evolving diagnosis and management: A scientific statement from the American Heart Association. Circulation 2020;142:e7‐e22. doi:10.1161/CIR.0000000000000792

Gilstrap LG, Dominici F, Wang Y, El‐Sady MS, Singh A, Di Carli MF, et al. Epidemiology of cardiac amyloidosis‐associated heart failure hospitalizations among fee‐for‐service Medicare beneficiaries in the United States. Circ Heart Fail 2019;12: [eLocator: e005407]. doi:10.1161/CIRCHEARTFAILURE.118.005407

Lane T, Fontana M, Martinez‐Naharro A, Quarta CC, Whelan CJ, Petrie A, et al. Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation 2019;140:16‐26. doi:10.1161/CIRCULATIONAHA.118.038169

Maurizi N, Rella V, Fumagalli C, Salerno S, Castelletti S, Dagradi F, et al. Prevalence of cardiac amyloidosis among adult patients referred to tertiary centres with an initial diagnosis of hypertrophic cardiomyopathy. Int J Cardiol 2020;300:191‐195. doi:10.1016/j.ijcard.2019.07.051

Writing Committee, Kittleson MM, Ruberg FL, Ambardekar AV, Brannagan TH, Cheng RK, et al. 2023 ACC expert consensus decision pathway on comprehensive multidisciplinary care for the patient with cardiac amyloidosis: A report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2023;81:1076‐1126. doi:10.1016/j.jacc.2022.11.022

U.S. Food and Drug Administration. Highlights of prescribing information: VYNDAQEL® (tafamidis meglumine) capsules, for oral administration; VYNDAMAX™ (tafamidis) capsules, for oral administration. https://www.fda.gov/media/126283/download. Accessed 29 May 2024

Burton A, Castaño A, Bruno M, Riley S, Schumacher J, Sultan MB, et al. Drug discovery and development in rare diseases: Taking a closer look at the tafamidis story. Drug Des Devel Ther 2021;15:1225‐1243. doi:10.2147/DDDT.S289772

European Medicines Agency. Summary of product characteristics: Vyndaqel 20 mg soft capsules, Vyndaqel 61 mg soft capsules. https://www.ema.europa.eu/en/documents/product‐information/vyndaqel‐epar‐product‐information_en.pdf. Accessed 29 May 2024

Pharmaceuticals and Medical Devices Agency. Package insert: Vyndaqel® capsules 20 mg (in Japanese). https://www.info.pmda.go.jp/go/pack/1290001M1022_2_04/. Accessed 29 May 2024

Takashio S, Morioka M, Ishii M, Morikawa K, Hirakawa K, Hanatani S, et al. Clinical characteristics, outcome, and therapeutic effect of tafamidis in wild‐type transthyretin amyloid cardiomyopathy. ESC Heart Fail 2023;10:2319‐2329. doi:10.1002/ehf2.14380

González‐López E, Gagliardi C, Dominguez F, Quarta CC, de Haro‐Del Moral FJ, Milandri A, et al. Clinical characteristics of wild‐type transthyretin cardiac amyloidosis: Disproving myths. Eur Heart J 2017;38:1895‐1904. doi:10.1093/eurheartj/ehx043

Gertz MA, Benson MD, Dyck PJ, Grogan M, Coelho T, Cruz M, et al. Diagnosis, prognosis, and therapy of transthyretin amyloidosis. J Am Coll Cardiol 2015;66:2451‐2466. doi:10.1016/j.jacc.2015.09.075

Yamamoto H, Yokochi T. Transthyretin cardiac amyloidosis: An update on diagnosis and treatment. ESC Heart Fail 2019;6:1128‐1139. doi:10.1002/ehf2.12518

Griffin JM, Rosenthal JL, Grodin JL, Maurer MS, Grogan M, Cheng RK. ATTR amyloidosis: Current and emerging management strategies: JACC: CardioOncology state‐of‐the‐art review. JACC CardioOncol 2021;3:488‐505. doi:10.1016/j.jaccao.2021.06.006

McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599‐3726. doi:10.1093/eurheartj/ehab368

Garcia‐Pavia P, Rapezzi C, Adler Y, Arad M, Basso C, Brucato A, et al. Diagnosis and treatment of cardiac amyloidosis: A position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2021;42:1554‐1568. doi:10.1093/eurheartj/ehab072

Yamada T, Takashio S, Arima Y, Nishi M, Morioka M, Hirakawa K, et al. Clinical characteristics and natural history of wild‐type transthyretin amyloid cardiomyopathy in Japan. ESC Heart Fail 2020;7:2829‐2837. doi:10.1002/ehf2.12884

Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2‐macroglobulin and tau: A population‐based autopsy study. Ann Med 2008;40:232‐239. doi:10.1080/07853890701842988

Grogan M, Scott CG, Kyle RA, Zeldenrust SR, Gertz MA, Lin G, et al. Natural history of wild‐type transthyretin cardiac amyloidosis and risk stratification using a novel staging system. J Am Coll Cardiol 2016;68:1014‐1020. doi:10.1016/j.jacc.2016.06.033

López‐Sainz Á, Hernandez‐Hernandez A, Gonzalez‐Lopez E, Domínguez F, Restrepo‐Cordoba MA, Cobo‐Marcos M, et al. Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center. Rev Esp Cardiol (Engl Ed) 2021;74:149‐158. doi:10.1016/j.rec.2019.12.020

Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, Charron P, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: The Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733‐2779. doi:10.1093/eurheartj/ehu284

Witteles RM, Bokhari S, Damy T, Elliott PM, Falk RH, Fine NM, et al. Screening for transthyretin amyloid cardiomyopathy in everyday practice. JACC Heart Fail 2019;7:709‐716. doi:10.1016/j.jchf.2019.04.010

Ton VK, Mukherjee M, Judge DP. Transthyretin cardiac amyloidosis: Pathogenesis, treatments, and emerging role in heart failure with preserved ejection fraction. Clin Med Insights Cardiol 2015;8:39‐44. doi:10.4137/CMC.S15719

Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016;133:2404‐2412. doi:10.1161/CIRCULATIONAHA.116.021612

González‐López E, Gallego‐Delgado M, Guzzo‐Merello G, de Haro‐Del Moral FJ, Cobo‐Marcos M, Robles C, et al. Wild‐type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J 2015;36:2585‐2594. doi:10.1093/eurheartj/ehv338

Nakagawa M, Sekijima Y, Yazaki M, Tojo K, Yoshinaga T, Doden T, et al. Carpal tunnel syndrome: A common initial symptom of systemic wild‐type ATTR (ATTRwt) amyloidosis. Amyloid 2016;23:58‐63. doi:10.3109/13506129.2015.1135792

Fosbøl EL, Rørth R, Leicht BP, Schou M, Maurer MS, Kristensen SL, et al. Association of carpal tunnel syndrome with amyloidosis, heart failure, and adverse cardiovascular outcomes. J Am Coll Cardiol 2019;74:15‐23. doi:10.1016/j.jacc.2019.04.054

Godara A, Riesenburger RI, Zhang DX, Varga C, Fogaren T, Siddiqui NS, et al. Association between spinal stenosis and wild‐type ATTR amyloidosis. Amyloid 2021;28:226‐233. doi:10.1080/13506129.2021.1950681

Westin O, Fosbøl EL, Maurer MS, Leicht BP, Hasbak P, Mylin AK, et al. Screening for cardiac amyloidosis 5 to 15 years after surgery for bilateral carpal tunnel syndrome. J Am Coll Cardiol 2022;80:967‐977. doi:10.1016/j.jacc.2022.06.026

Ladefoged B, Clemmensen T, Dybro A, Hartig‐Andreasen C, Kirkeby L, Gormsen LC, et al. Identification of wild‐type transthyretin cardiac amyloidosis in patients with carpal tunnel syndrome surgery (CACTuS). ESC Heart Fail 2023;10:234‐244. doi:10.1002/ehf2.14173

Ikura H, Kitakata H, Endo J. A reliable baton passing from orthopedic surgeon to cardiologist ‐ cardiac screening in patients with carpal tunnel syndrome for early diagnosis of transthyretin amyloid cardiomyopathy. Circ J 2023;87:1056‐1057. doi:10.1253/circj.CJ‐23‐0453

Takashio S, Kato T, Tashima H, Irie H, Komohara Y, Oguni T, et al. Prevalence of cardiac amyloidosis in patients undergoing carpal tunnel release with amyloid deposition. Circ J 2023;87:1047 ‐1055. doi:10.1253/circj.CJ‐23‐0223

Goda A, Masuyama T. Obesity and overweight in Asian people. Circ J 2016;80:2425‐2426. doi:10.1253/circj.CJ‐16‐1087

Chacko L, Martone R, Bandera F, Lane T, Martinez‐Naharro A, Boldrini M, et al. Echocardiographic phenotype and prognosis in transthyretin cardiac amyloidosis. Eur Heart J 2020;41:1439‐1447. doi:10.1093/eurheartj/ehz905

Arvidsson S, Henein MY, Wikstrom G, Suhr OB, Lindqvist P. Right ventricular involvement in transthyretin amyloidosis. Amyloid 2018;25:160‐166. doi:10.1080/13506129.2018.1493989

Boldrini M, Cappelli F, Chacko L, Restrepo‐Cordoba MA, Lopez‐Sainz A, Giannoni A, et al. Multiparametric echocardiography scores for the diagnosis of cardiac amyloidosis. JACC Cardiovasc Imaging 2020;13:909‐920. doi:10.1016/j.jcmg.2019.10.011

Ota S, Izumiya Y, Kitada R, Nishi T, Taruya A, Wada T, et al. Diagnostic significance of paradoxical left ventricular hypertrophy in detecting cardiac amyloidosis. Int J Cardiol Heart Vasc 2023;49: [eLocator: 101279]. doi:10.1016/j.ijcha.2023.101279

Rahman JE, Helou EF, Gelzer‐Bell R, Thompson RE, Kuo C, Rodriguez ER, et al. Noninvasive diagnosis of biopsy‐proven cardiac amyloidosis. J Am Coll Cardiol 2004;43:410‐415. doi:10.1016/j.jacc.2003.08.043

Martinez‐Naharro A, Kotecha T, Norrington K, Boldrini M, Rezk T, Quarta C, et al. Native T1 and extracellular volume in transthyretin amyloidosis. JACC Cardiovasc Imaging 2019;12:810‐819. doi:10.1016/j.jcmg.2018.02.006

Deux JF, Nouri R, Tacher V, Zaroui A, Derbel H, Sifaoui I, et al. Diagnostic value of extracellular volume quantification and myocardial perfusion analysis at CT in cardiac amyloidosis. Radiology 2021;300:326‐335. doi:10.1148/radiol.2021204192

Kidoh M, Oda S, Takashio S, Hirakawa K, Kawano Y, Shiraishi S, et al. CT extracellular volume fraction versus myocardium‐to‐lumen signal ratio for cardiac amyloidosis. Radiology 2023;306: [eLocator: e220542]. doi:10.1148/radiol.220542

Yamasaki H, Kondo H, Shiroo T, Iwata N, Masuda T, Makita T, et al. Efficacy of computed tomography‐based evaluation of myocardial extracellular volume combined with red flags for early screening of concealed cardiac amyloidosis in patients with atrial fibrillation. Circ J 2024;88:1167‐1175. doi:10.1253/circj.CJ‐23‐0948

Scully PR, Patel KP, Saberwal B, Klotz E, Augusto JB, Thornton GD, et al. Identifying cardiac amyloid in aortic stenosis: ECV quantification by CT in TAVR patients. JACC Cardiovasc Imaging 2020;13:2177‐2189. doi:10.1016/j.jcmg.2020.05.029

Oda S, Kidoh M, Takashio S, Inoue T, Nagayama Y, Nakaura T, et al. Quantification of myocardial extracellular volume with planning computed tomography for transcatheter aortic valve replacement to identify occult cardiac amyloidosis in patients with severe aortic stenosis. Circ Cardiovasc Imaging 2020;13: [eLocator: e010358]. doi:10.1161/CIRCIMAGING.119.010358

Takashio S, Yamamuro M, Izumiya Y, Hirakawa K, Marume K, Yamamoto M, et al. Diagnostic utility of cardiac troponin T level in patients with cardiac amyloidosis. ESC Heart Fail 2018;5:27‐35. doi:10.1002/ehf2.12203

Kubo T, Baba Y, Hirota T, Tanioka K, Yamasaki N, Yamanaka S, et al. Differentiation of infiltrative cardiomyopathy from hypertrophic cardiomyopathy using high‐sensitivity cardiac troponin T: A case‐control study. BMC Cardiovasc Disord 2015;15:53. doi:10.1186/s12872‐015‐0043‐z

Marume K, Takashio S, Nishi M, Hirakawa K, Yamamoto M, Hanatani S, et al. Combination of commonly examined parameters is a useful predictor of positive ^99mTc‐labeled pyrophosphate scintigraphy findings in elderly patients with suspected transthyretin cardiac amyloidosis. Circ J 2019;83:1698‐1708. doi:10.1253/circj.CJ‐19‐0255

Vergaro G, Castiglione V, Aimo A, Prontera C, Masotti S, Musetti V, et al. N‐terminal pro‐B‐type natriuretic peptide and high‐sensitivity troponin T hold diagnostic value in cardiac amyloidosis. Eur J Heart Fail 2023;25:335‐346. doi:10.1002/ejhf.2769

Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state‐of‐the‐art review. J Am Coll Cardiol 2019;73:2872‐2891. doi:10.1016/j.jacc.2019.04.003

Giancaterino S, Urey MA, Darden D, Hsu JC. Management of arrhythmias in cardiac amyloidosis. JACC Clin Electrophysiol 2020;6:351‐361. doi:10.1016/j.jacep.2020.01.004

Donnellan E, Wazni O, Kanj M, Elshazly MB, Hussein A, Baranowski B, et al. Atrial fibrillation ablation in patients with transthyretin cardiac amyloidosis. Europace 2020;22:259‐264. doi:10.1093/europace/euz314

Hartnett J, Jaber W, Maurer M, Sperry B, Hanna M, Collier P, et al. Electrophysiological manifestations of cardiac amyloidosis: JACC: CardioOncology state‐of‐the‐art review. JACC CardioOncol 2021;3:506‐515. doi:10.1016/j.jaccao.2021.07.010

Gillmore JD, Damy T, Fontana M, Hutchinson M, Lachmann HJ, Martinez‐Naharro A, et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J 2018;39:2799‐2806. doi:10.1093/eurheartj/ehx589

Cannie D, Patel K, Protonotarios A, Heenan I, Bakalakos A, Syrris P, et al. Prevalence of transthyretin cardiac amyloidosis in patients with high‐degree AV block. Open Heart 2024;11: [eLocator: e002606]. doi:10.1136/openhrt‐2024‐002606

Donnellan E, Wazni OM, Saliba WI, Baranowski B, Hanna M, Martyn M, et al. Cardiac devices in patients with transthyretin amyloidosis: Impact on functional class, left ventricular function, mitral regurgitation, and mortality. J Cardiovasc Electrophysiol 2019;30:2427‐2432. doi:10.1111/jce.14180

Donnellan E, Wazni OM, Saliba WI, Hanna M, Kanj M, Patel DR, et al. Prevalence, incidence, and impact on mortality of conduction system disease in transthyretin cardiac amyloidosis. Am J Cardiol 2020;128:140‐146. doi:10.1016/j.amjcard.2020.05.021

Dorbala S, Vangala D, Bruyere J Jr, Quarta C, Kruger J, Padera R, et al. Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis. JACC Heart Fail 2014;2:358‐367. doi:10.1016/j.jchf.2014.03.009

Takashio S, Yamamuro M, Izumiya Y, Sugiyama S, Kojima S, Yamamoto E, et al. Coronary microvascular dysfunction and diastolic load correlate with cardiac troponin T release measured by a highly sensitive assay in patients with nonischemic heart failure. J Am Coll Cardiol 2013;62:632‐640. doi:10.1016/j.jacc.2013.03.065

İrgi T, Baycan ÖF, Güvenç TS, Özcan FB, Atıcı A, Yılmaz Y, et al. Concomitant amyloidosis is the primary cause of endothelial and coronary microvascular dysfunction in carpal tunnel syndrome. Am Heart J Plus 2024;41: [eLocator: 100393]. doi:10.1016/j.ahjo.2024.100393

Hokimoto S, Kaikita K, Yasuda S, Tsujita K, Ishihara M, Matoba T, et al. JCS/CVIT/JCC 2023 guideline focused update on diagnosis and treatment of vasospastic angina (coronary spastic angina) and coronary microvascular dysfunction. Circ J 2023;87:879‐936. doi:10.1253/circj.CJ‐22‐0779

Del Buono MG, Montone RA, Camilli M, Carbone S, Narula J, Lavie CJ, et al. Coronary microvascular dysfunction across the spectrum of cardiovascular diseases: JACC state‐of‐the‐art review. J Am Coll Cardiol 2021;78:1352‐1371. doi:10.1016/j.jacc.2021.07.042

Castaño A, Narotsky DL, Hamid N, Khalique OK, Morgenstern R, DeLuca A, et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur Heart J 2017;38:2879‐2887. doi:10.1093/eurheartj/ehx350

Rosenblum H, Masri A, Narotsky DL, Goldsmith J, Hamid N, Hahn RT, et al. Unveiling outcomes in coexisting severe aortic stenosis and transthyretin cardiac amyloidosis. Eur J Heart Fail 2021;23:250‐258. doi:10.1002/ejhf.1974

Dobner S, Pilgrim T, Hagemeyer D, Heg D, Lanz J, Reusser N, et al. Amyloid transthyretin cardiomyopathy in elderly patients with aortic stenosis undergoing transcatheter aortic valve implantation. J Am Heart Assoc 2023;12: [eLocator: e030271]. doi:10.1161/JAHA.123.030271

Cavalcante JL, Rijal S, Abdelkarim I, Althouse AD, Sharbaugh MS, Fridman Y, et al. Cardiac amyloidosis is prevalent in older patients with aortic stenosis and carries worse prognosis. J Cardiovasc Magn Reson 2017;19:98. doi:10.1186/s12968‐017‐0415‐x

Ternacle J, Krapf L, Mohty D, Magne J, Nguyen A, Galat A, et al. Aortic stenosis and cardiac amyloidosis: JACC review topic of the week. J Am Coll Cardiol 2019;74:2638‐2651. doi:10.1016/j.jacc.2019.09.056

Jaiswal V, Agrawal V, Khulbe Y, Hanif M, Huang H, Hameed M, et al. Cardiac amyloidosis and aortic stenosis: A state‐of‐the‐art review. Eur Heart J Open 2023;3: [eLocator: oead106]. doi:10.1093/ehjopen/oead106

Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: Executive summary: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022;79:1757‐1780. doi:10.1016/j.jacc.2021.12.011

McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2022;24:4‐131. doi:10.1002/ejhf.2333

Maurer MS, Mann DL. The tafamidis drug development program: A translational triumph. JACC Basic Transl Sci 2018;3:871‐873. doi:10.1016/j.jacbts.2018.10.001

Elliott P, Drachman BM, Gottlieb SS, Hoffman JE, Hummel SL, Lenihan DJ, et al. Long‐term survival with tafamidis in patients with transthyretin amyloid cardiomyopathy. Circ Heart Fail 2022;15: [eLocator: e008193]. doi:10.1161/CIRCHEARTFAILURE.120.008193

Ochi Y, Kubo T, Baba Y, Sugiura K, Miyagawa K, Noguchi T, et al. Early experience of tafamidis treatment in Japanese patients with wild‐type transthyretin cardiac amyloidosis from the Kochi amyloidosis cohort. Circ J 2022;86:1121‐1128. doi:10.1253/circj.CJ‐21‐0965

Ichikawa Y, Oota E, Odajima S, Kintsu M, Todo S, Takeuchi K, et al. Impact of tafamidis on echocardiographic cardiac function of patients with transthyretin cardiac amyloidosis. Circ J 2023;87:508‐516. doi:10.1253/circj.CJ‐22‐0683

Ioannou A, Massa P, Patel RK, Razvi Y, Porcari A, Rauf MU, et al. Conventional heart failure therapy in cardiac ATTR amyloidosis. Eur Heart J 2023;44:2893‐2907. doi:10.1093/eurheartj/ehad347

Aimo A, Vergaro G, Castiglione V, Rapezzi C, Emdin M. Safety and tolerability of neurohormonal antagonism in cardiac amyloidosis. Eur J Intern Med 2020;80:66‐72. doi:10.1016/j.ejim.2020.05.015

Barge‐Caballero G, Barge‐Caballero E, López‐Pérez M, Bilbao‐Quesada R, González‐Babarro E, Gómez‐Otero I, et al. Beta‐blocker exposure and survival in patients with transthyretin amyloid cardiomyopathy. Mayo Clin Proc 2022;97:261‐273. doi:10.1016/j.mayocp.2021.08.006

Dobner S, Bernhard B, Asatryan B, Windecker S, Stortecky S, Pilgrim T, et al. SGLT2 inhibitor therapy for transthyretin amyloid cardiomyopathy: Early tolerance and clinical response to dapagliflozin. ESC Heart Fail 2023;10:397‐404. doi:10.1002/ehf2.14188

Zampieri M, Argiro A, Allinovi M, Perfetto F, Cappelli F. SGLT2i in patients with transthyretin cardiac amyloidosis, a well‐tolerated option for heart failure treatment? Results from a small, real‐world, patients series. Intern Emerg Med 2022;17:1243‐1245. doi:10.1007/s11739‐022‐02944‐8

Cappelli F, Martone R, Gabriele M, Taborchi G, Morini S, Vignini E, et al. Biomarkers and prediction of prognosis in transthyretin‐related cardiac amyloidosis: Direct comparison of two staging systems. Can J Cardiol 2020;36:424‐431. doi:10.1016/j.cjca.2019.12.020

Ioannou A, Rauf MU, Patel RK, Razvi Y, Porcari A, Martinez‐Naharro A, et al. Albuminuria in transthyretin cardiac amyloidosis: Prevalence, progression and prognostic importance. Eur J Heart Fail 2024;26:65‐73. doi:10.1002/ejhf.3094

Donnellan E, Wazni OM, Hanna M, Elshazly MB, Puri R, Saliba W, et al. Atrial fibrillation in transthyretin cardiac amyloidosis: Predictors, prevalence, and efficacy of rhythm control strategies. JACC Clin Electrophysiol 2020;6:1118‐1127. doi:10.1016/j.jacep.2020.04.019

Hanatani A, Shibata A, Kitada R, Iwata S, Matsumura Y, Doi A, et al. Administration of tolvaptan with reduction of loop diuretics ameliorates congestion with improving renal dysfunction in patients with congestive heart failure and renal dysfunction. Heart Vessels 2017;32:287‐294. doi:10.1007/s00380‐016‐0872‐4

Damman K, Kjekshus J, Wikstrand J, Cleland JG, Komajda M, Wedel H, et al. Loop diuretics, renal function and clinical outcome in patients with heart failure and reduced ejection fraction. Eur J Heart Fail 2016;18:328‐336. doi:10.1002/ejhf.462

Monoe C, Shimizu H, Kitaguchi K, Funakoshi H. Severe bradycardia induced by sofosbuvir and amiodarone which resolved after the discontinuation of both drugs. Intern Med 2020;59:2619‐2622. doi:10.2169/internalmedicine.4488‐20

Okamoto N, Kubo T, Nakashima Y, Ochi Y, Takahashi A, Baba Y, et al. Beneficial effect of pimobendan for severe heart failure due to transthyretin cardiac amyloidosis. Intern Med 2020;59:339‐343. doi:10.2169/internalmedicine.3675‐19

Negreira‐Caamaño M, Martínez‐Del Río J, Morón‐Alguacil A, Pérez‐Díaz P, Piqueras‐Flores J. Starting sacubitril‐valsartan is safe in patients with transthyretin cardiac amyloidosis and impaired ejection fraction. Rev Port Cardiol 2023;42:183‐186. doi:10.1016/j.repc.2022.12.008

Fowler B, Vincenzi A, Vullo E, Fagnani A, Lettino M. P218 wild type transthyretin cardiac amyloidosis (wtATTR) and heart failure with reduced ejection fraction (HFrEF): Can angiotensin receptor/neprilysin inhibitors (ARNI) be a therapeutic option? Eur Heart J Suppl 2023;25:D123. doi:10.1093/eurheartjsupp/suad111.293

Porcari A, Rossi M, Cappelli F, Canepa M, Musumeci B, Cipriani A, et al. Incidence and risk factors for pacemaker implantation in light‐chain and transthyretin cardiac amyloidosis. Eur J Heart Fail 2022;24:1227‐1236. doi:10.1002/ejhf.2533

Kim EJ, Holmes BB, Huang S, Lugo R, Al Aboud A, Goodman S, et al. Outcomes in patients with cardiac amyloidosis and implantable cardioverter‐defibrillator. Europace 2020;22:1216‐1223. doi:10.1093/europace/euaa094

Kawahara Y, Kanazawa H, Takashio S, Tsuruta Y, Sumi H, Kiyama T, et al. Clinical, electrocardiographic, and echocardiographic parameters associated with the development of pacing and implantable cardioverter‐defibrillator indication in patients with transthyretin amyloid cardiomyopathy. Europace 2023;25: [eLocator: euad105]. doi:10.1093/europace/euad105

Dale Z, Al‐Rashdan L, Elman M, Chandrashekar P, Heitner SB, Nazer B, et al. Mode of death and outcomes of implantable cardioverter defibrillators in transthyretin amyloid cardiomyopathy. Int J Cardiol 2022;349:99‐102. doi:10.1016/j.ijcard.2021.11.057

Donnellan E, Wazni OM, Hanna M, Kanj M, Saliba WI, Jaber WA. Cardiac resynchronization therapy for transthyretin cardiac amyloidosis. J Am Heart Assoc 2020;9: [eLocator: e017335]. doi:10.1161/JAHA.120.017335