Review Article

Heart Failure Management in Cardiac Amyloidosis: Towards a Paradigm Shift

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Abstract

Heart failure (HF) and cardiac amyloidosis (CA) are significant clinical challenges, with evolving epidemiological patterns reshaping the understanding of these conditions. Traditionally linked with HF with preserved ejection fraction, CA is increasingly recognised for its specific characteristics, including a considerable subset of patients presenting with reduced left ventricular ejection fraction. This review explores how the neurohormonal activation observed in CA impacts on disease progression and management strategies. Historically, neurohormonal antagonists were considered contraindicated in CA owing to concerns about autonomic dysfunction and chronotropic incompetence. However, recent evidence suggests a paradigm shift, indicating that such agents may offer therapeutic benefits even in these patients. By examining these developments, this review provides a comprehensive overview of current therapeutic approaches, the role of neurohormonal modulation and the need for personalised care strategies to address the complexities of HF in the context of CA.

Keywords

Heart failure, cardiac amyloidosis, neurohormonal, β-blockers,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/cfr.2024.33

Disclosure: The authors have no conflicts of interest to declare.

Correspondence: Michele Emdin, Fondazione Toscana Gabriele Monasterio, Via Giuseppe Moruzzi 1, 56124, Pisa, Italy. E: m.emdin@santannapisa.it

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Cardiac amyloidosis (CA) is an increasingly recognised cause of heart failure (HF); it results from the deposition of amyloid fibrils within the myocardium and leads to progressive cardiac dysfunction.1 CA can result from various types of amyloid proteins, with transthyretin CA (ATTR-CA) and light-chain CA (AL-CA) being the most prevalent forms affecting the heart.

The deposition of these amyloid fibrils disrupts the normal architecture and function of the heart, leading to restrictive cardiomyopathy, arrhythmias and HF. This condition, while less common than other HF aetiologies, poses a significant challenge owing to its complex pathophysiology and the severe impact it has on cardiac function.

In recent years, novel pharmacological treatments and targeted therapies have been transforming the management of CA, offering hope for improved outcomes. Therapies targeting the amyloidogenic cascade can modify the natural history of the disease, albeit only after a period of latency following treatment initiation (for example, around 18 months after starting tafamidis to impact on all-cause mortality).2

Cardiac involvement remains a crucial determinant of morbidity and mortality, and the evolution of this is partially independent from the underlying disorder. Supportive therapies may play a key role in counteracting cardiac remodelling and preserving cardiac function, mitigating the progression of HF while disease-modifying treatments gradually take effect.

Conventional HF therapies have been traditionally contraindicated in CA patients. This is attributed to poor haemodynamic tolerance of these therapies because of an altered pressure–volume loop, potential ventricular–vascular decoupling and chronotropic incompetence.3 However, consensus documents recommendations rely upon weak evidence and expert opinion.4

Recent evidence suggests there has been a paradigm shift in managing HF in these patients, with a potential benefit from some neurohormonal drugs at least in ATTR-CA and/or in the early stage of the disease.

This review aims to explore the evolving epidemiology of HF and CA, focusing on understanding the role of neurohormonal activation in CA and its implications. Additionally, it will evaluate current therapeutic strategies for managing CA, while also addressing comorbidities and complications associated with HF (Figure 1).

Figure 1: Heart Failure Treatment in Cardiac Amyloidosis

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Epidemiology

Within the spectrum of HF aetiologies, CA represents a critical but often overlooked cause of HF. While CA accounts for a relatively small proportion of HF cases overall, its prevalence is markedly higher in some groups, notably in elderly populations and individuals with CA red flags.5,6 Conversely, HF is a common manifestation in patients with CA as amyloid infiltration compromises cardiac structure and function.

Until recently, epidemiological studies on CA were primarily single-centre and limited in sample size. However, a recent Spanish prospective multicentre study evaluated the prevalence of CA among 453 patients aged ≥65 years with HF and a left ventricular (LV) wall thickness >12 mm.7 CA was diagnosed based on current recommendations in one in five (20.1%) patients, with ATTR-CA in 84.6% and a higher prevalence in men (60.1% versus 39.9%; p=0.019). In this series, 26.5% of the patients with CA had a LV ejection fraction (LVEF) of <50%.7

In a previous study by Lindmark et al., 20% of 134 investigated patients in a Swedish cohort with HF and an LV wall thickness >14 mm had wild-type ATTR-CA (ATTRwt-CA).8 Calculated for the whole population of HF patients, the prevalence is just over 1.1%. Comparing this number to the total population would give an estimated prevalence of 1:6,000.8

CA has been traditionally associated with HF with preserved ejection fraction (HFpEF), owing to extracellular accumulation of misfolded protein fragments causing a restrictive filling pattern. The reported prevalence of CA in HFpEF is in the range of 5–14%.9–11 In a study by Hahn et al., 108 patients with HFpEF were prospectively subjected to endomyocardial biopsy. CA was diagnosed in 15 (14%) patients: seven patients with ATTRwt-CA; four with variant CA (ATTRv-CA); three with AL-CA; and one patient with AA amyloidosis.12 Patients with HFpEF-CA were older, with a lower BMI, higher LV mass index and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin I levels.12

In a cohort of elderly patients with HFpEF without LV hypertrophy (LV wall thickness <12 mm), the prevalence of ATTRwt-CA was 5%.13 A prospective study using bone scintigraphy to screen for ATTR-CA in HFpEF patients showed that ATTRwt amyloidosis accounts for 13% of patients with LV hypertrophy aged >60 years hospitalised for HFpEF.

Finally, in a cohort of 1,235 patients with HFpEF (LVEF ≥40%) aged ≥60 years and with an LV wall thickness of ≥12 mm, CA was diagnosed in 16 patients (1.3%); prevalence increased from 0% in patients aged 60–69 years old to 21% in those aged ≥90 years (p<0.001).14

Nonetheless, CA is emerging as an important cause of HF with reduced EF (HFrEF). In a systematic review including 11 studies and 3,303 patients, the pooled prevalence of CA in HF was 13.7%. The overall prevalence of CA in HFpEF was 15.1%, and that of HFrEF was 11.3%. The main factors associated with a diagnosis of CA in HF included older age, being male, raised NT-proBNP, increased interventricular septal thickness, apical sparing and reduced LV systolic function.15

The epidemiology of CA is steadily expanding and evolving, driven by increased awareness of red flags for CA and the possibility of a non-invasive diagnosis through the algorithm by Gilmore et al.16,17 This trend is further influenced by the rising life expectancy of the general population and the introduction of disease-modifying therapies.

Advances in non-invasive diagnostic modalities and serum biomarkers have significantly enhanced the detection of CA among HF patients. Recognising the bidirectional relationship between HF and CA is crucial for timely diagnosis and appropriate therapeutic intervention.

Neurohormonal Activation

Over the decades, our understanding of HF has evolved considerably. Until the 1960s, HF was seen mainly as a cardiorenal disorder, primarily linked to sodium retention by the kidneys, resulting in increased fluid volume and thus leading to pulmonary and/or peripheral oedema.18

In the 1960s to the 1980s, the perspective shifted to a haemodynamic model, with an emphasis on the roles of reduced contractility and peripheral vasoconstriction in symptom occurrence and exercise intolerance. 18

In the 1990s, HF was reinterpreted as a neurohormonal disorder, highlighting the role of activated endogenous neurohormonal mechanisms in disease progression.18 Neurohormonal activation in HF is a critical factor in the pathophysiology and progression of the disease. Among these systems, the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS) are particularly significant.19

The SNS plays a pivotal role in HF by increasing catecholamine levels, which cause excessive vasoconstriction, persistent tachycardia and cardiac arrhythmias. Elevated plasma catecholamines, resulting from heightened SNS activity, lead to a reduction in β-adrenergic receptor density within the failing myocardium, thereby diminishing the heart’s responsiveness to inotropic and chronotropic stimuli.20

Chronic SNS activation also depletes the norepinephrine stores in the heart, forcing reliance on circulating catecholamines to maintain cardiac output, which contributes to a vicious cycle of worsening HF.21

Finally, increased sympathetic activity is associated with chronotropic incompetence, which is characterised by an insufficient increase in the heart rate during exercise. This may result from β-adrenergic receptor downregulation, β-blocker use or high-baseline heart rates, and leads to exercise intolerance and reduced exercise capacity.22

The RAAS promotes sodium and water retention, vasoconstriction and myocardial fibrosis. Overactivation of the RAAS leads to the production of angiotensin II, a potent vasoconstrictor, which raises blood pressure and contributes to adverse cardiac remodelling. Additionally, aldosterone promotes myocardial fibrosis and endothelial dysfunction.23

Pharmacological interventions targeting the RAAS, including angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs) and the more recent angiotensin receptor-neprilysin inhibitor (ARNi) sacubitril/valsartan, have proven highly effective in improving clinical outcomes in HF patients.24–26 Mineralocorticoid receptor antagonists (MRAs) inhibit aldosterone’s action, leading to reduced sodium and water retention, decreased blood pressure and improved outcomes in HF.27 All these agents not only reduce mortality and hospitalisation rates but also help reverse maladaptive cardiac remodelling.

The pathophysiology of HFpEF differs from that of HFrEF, with neurohormonal activation having a much less prominent role. Accordingly, all neurohormonal antagonists have failed to prolong the survival of patients with HFpEF in large randomised trials.28,29

Despite its typical presentation with a hypertrophic phenotype, CA cannot be assimilated to HFpEF for many reasons, including its different pathophysiology (with an extracellular accumulation of amyloid fibrils producing a pseudohypertrophy) and natural history. Furthermore, the effects of AL-CA and ATTR-CA on the neurohormonal axes might be partially different, with a greater toxic effect of light-chain than transthyretin fibrils, causing cardiomyocyte damage and increased wall stress (both leading to natriuretic peptide release), a more rapid development of cardiac dysfunction (with the need of SNS and RAAS activation to sustain haemodynamics) and a direct toxic effect of light-chain amyloid fibrils on cardiac sympathetic terminals.30

Neurohormonal activation in CA was researched for the first time in a study by Vergaro et al.30 The authors matched 47 patients with AL-CA and 61 with ATTR-CA to HF patients based on age, sex, LVEF ranges, renal function and HF therapies. Patients with AL-CA had: a 10-fold higher NT-proBNP than HF patients (6,548 ng/l; 95% CI [2,059–15,097] versus 692; 95% CI [243–2,241]; p<0.001); and slightly higher norepinephrine (595 ng/l; 95% CI [383–869] versus 416; 95% CI [250–693]; p=0.047). Patients with ATTR-CA had: higher NT-proBNP (3,984 ng/l; 95% CI [2,275–9,505] versus 1,751 ng/l; 95% CI [470–4,768]; p=0.006); norepinephrine (552 ng/l; 95% CI [344–855] versus 441; 95% CI [323–601]; p=0.020), and renin (14 mU/l; 95% CI [8–80] versus 10 mU/l; 95% CI [4–34]; p=0.017).

Patients with AL-CA or ATTR-CA more often had two or three neurohormones above the corresponding upper reference limits than matched HF patients. NT-proBNP and aldosterone were univariate predictors of the primary endpoint of 1-year cardiovascular death or HF hospitalisation in patients with ATTR-CA, but not in matched controls. NT-proBNP and renin predicted the secondary endpoint of 5-year cardiovascular death in patients with AL-CA, but not in matched controls.

These findings show that CA patients have a higher neurohormonal activation than non-CA HF patients and confirm the prognostic value of NT-proBNP in ATTR-CA, thus suggesting the potential benefit of MRAs or ARNis in patients with ATTR-CA.31

Therapeutic Strategies

Therapies targeting the amyloidogenic cascade can modify the natural history of the disease, albeit only after a period of latency following treatment. In the meantime, cardiac involvement remains a crucial determinant of morbidity and mortality, and its evolution is partially independent from the underlying disorder.

Four Pillars

Historically, the use of β-blockers and ACEi/ARB/ARNis has been contraindicated in CA by most consensus documents (Table 1).4

Table 1: Recommendations for Drugs for Heart Failure in Cardiac Amyloidosis

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β-blockers are theorised to be poorly tolerated in people with CA because of patients’ fixed stroke volume and dependence on a chronotropic response to maintain cardiac output.1 This is especially critical in cases with overt restrictive physiology, where cardiac output relies heavily on heart rate.32

Additionally, ACEi/ARB/ARNis are believed to exacerbate hypotension from amyloid-associated autonomic dysfunction in AL-CA and ATTRv-CA.33 Similarly, they can also be poorly tolerated, particularly in patients who are hypotensive. A retrospective study indicated no survival benefit from β-blocker or ACEi/ARB therapy in patients with ATTR-CA.34 Moreover, β-blocker discontinuation seemed to be associated with decreased mortality.34

Several consensus guidelines advise against the use of β-blockers or ACEi/ARBs, and the European Society of Cardiology (ESC) position statement suggests to deprescribe β-blockers and avoid ACEi/ARBs in all patients.35 However, nearly 30% of patients in the ATTR-ACT trial were receiving β-blockers or ACEi/ARBs.2

In a study on 99 patients with CA (72% men; mean age 80 years; 33% AL-CA and 67% ATTR-CA), β-blockers were successfully prescribed in up to 87% of patients, ACEi/ARB in up to 75% and MRAs in up to 63%.36 Furthermore, the vast majority of patients tolerated these therapies without major adverse events, provided that no contraindications were present, and that the medications were initiated at low doses, gradually uptitrated and closely monitored.36

Similar results supporting the safe use of HF therapies in CA patients with HFrEF or HF with mid-range EF were reported in a study by Yan et al., where ARNis were also included.37 The study showed no statistically significant differences in rates of potential adverse effects in treated versus untreated patients. Moreover, there was no association with hospitalisation or mortality for baseline or follow-up β-blocker, ACEi/ARB/ARNi or MRA use.37

As stated above, patients with CA exhibit greater neurohormonal activation than those with HF, and this activation may contribute to the progression of cardiac disease over time.30 Additionally, endomyocardial biopsies from patients with CA show significant fibrosis, which may influence the clinical manifestations of heart disease and could potentially be mitigated by antifibrotic drugs such as ACEis/ARBs or MRAs.38

Besides these considerations, a recent study by Ioannou et al. characterised HF treatment in over 2,000 patients with ATTR-CA followed at the National Amyloidosis Centre over 2000–22.39 Patients with a more severe cardiac phenotype were found to be more frequently treated with HF medications. During a median follow-up of 27.8 months, 21.7% of patients discontinued β-blockers and 32.9% discontinued ACEi/ARBs compared to only 7.5% for MRAs. Propensity score-matched analysis showed that MRAs were independently associated with a reduced risk of mortality in the overall population (HR 0.77; 95% CI [0.66–0.89]; p<0.001) and in patients with LVEF >40% (HR 0.75; 95% CI [0.63–0.90]; p=0.002).

This is in line with a retrospective analysis of the TOPCAT trial in a subcohort enriched for echocardiographic characteristics consistent with CA.40 Low-dose β-blockers were associated with reduced mortality in patients with an LVEF ≤40% (HR 0.61; 95% CI [0.45–0.83]; p=0.002), while ACEis/ARBs showed no significant benefit.39

These results suggest that MRAs and low-dose β-blockers may offer a survival benefit in ATTR-CA, challenging current recommendations. The relative risk reduction with β-blockers and MRAs is similar to that demonstrated in the ATTR-ACT study with tafamidis for all-cause mortality, but at a much lower medication cost.2,3 However, randomised controlled trials would be needed to investigate further these therapies in ATTR-CA.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been shown to improve the outcome of patients with HF with either preserved or reduced EF, but patients with CA have been excluded from all phase III trials on empagliflozin and dapagliflozin.41–44

The slight diuretic effect and multiple proposed cardiac-protective mechanisms may prove beneficial even in patients with CA.45 A small, single-centre, retrospective study compared patients with ATTR-CA and on tafamidis (n=40) with patients on tafamidis who were starting dapagliflozin (n=17). Over 3 months, dapagliflozin was well tolerated but changes in NT-proBNP did not differ between the two groups (p=0.557).46

In a recent multicentre, longitudinal, observational study performed across 14 referral centres for CA, 220 ATTR-CA patients treated with SGLT2i (mean age: 77 years; mean LVEF: 46%) were compared to 220 propensity-matched controls.47 SGLT2i treatment in ATTR-CA patients was well tolerated, with only 4.5% of patients discontinuing therapy. Moreover, it was associated with a decreased rate of worsening in HF symptoms, less increase in NT-proBNP, a slower decline in renal function and a lower diuretic agent requirement over time.

Over 28 months, SGLT2i therapy was associated with lower all-cause mortality (HR 0.57; 95% CI [0.37–0.89]; p=0.010), cardiovascular mortality (HR 0.41; 95% CI [0.24–0.71]; p<0.001), HF hospitalisation (HR 0.57; 95% CI [0.36–0.91]; p=0.014), and the composite outcome of cardiovascular mortality and HF hospitalisation (HR 0.57; 95% CI [0.38–0.84]; p=0.003).47

In a recent, small-scale, retrospective study on patients with AL-CA, SGLT2i therapy was generally well tolerated, though some patients experienced volume depletion symptoms that required temporary discontinuation.48 The therapy was associated with reductions in diuretic dosage and NT-proBNP levels (p<0.05), suggesting potential benefits in patients with AL-CA who have symptomatic HF and/or high diuretic requirement.48

The evidence on the safety and efficacy of HF therapies in CA is outlined in Table 2.

Table 2: Characteristics of the Studies Investigating Safety and Efficacy of Heart Failure Medications in Cardiac Amyloidosis

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Diuretics, Inotropes and Inodilators

Patients with CA usually have dyspnoea and tissue oedema because of increased pressures in the pulmonary vessels and the venous system. Diuretics (loop diuretics and MRAs) are often needed in high doses, are well tolerated and may be combined. In AL-CA, diuretics are the cornerstone of therapy since autonomic dysfunction often hinders the use of RAAS inhibitors.49

Diuretic dose has also been demonstrated to be a strong independent prognostic measure in ATTR-CA patients. A daily mean diuretic dose of 0.6 ± 1.0 mg/kg was associated with all-cause mortality (adjusted HR 1.43; 95% CI [1.06–1.93]) in a cohort of 309 patients with ATTR-CA. Moreover, adding diuretic dose as categories (0 mg/kg; >0–0.5 mg/kg; >0.5–1 mg/kg; and >1–2 mg/kg) to previously published ATTR risk scores provided significant incremental value (the area under the curve of the Mayo risk score increased from 0.693 to 0.767 and the UK risk score from 0.711 to 0.787).50

Care should be taken to avoid worsening renal function, electrolyte disturbances and excessive preload reduction.

There is also evidence that ambulatory diuresis clinics are safe and feasible management strategies in these patients, often reducing acute care need.51

The evidence about inotropes and inodilator therapy in CA is very limited. In a small, retrospective cohort of patients with CA receiving levosimendan during an episode of acute HF, according to clinical indication, levosimendan proved to be well tolerated and safe, though with a limited impact on in-hospital and post-discharge outcome.52

Even in patients with cardiogenic shock, inotropic therapy does not seem to improve outcome. In a single-centre, retrospective study, 26 patients with CA were admitted to the intensive care unit because of cardiogenic shock. Dobutamine was administered to 21 of them, with norepinephrine added in 10 of these patients; two were switched from dobutamine to levosimendan. The response to inotrope therapy was poor, with 17 patients (81%) dying during hospitalisation and the other four (15%) within 3 months.53

Digoxin, a cardiac glycoside, exerts its positive inotropic effects by reversely inhibiting the myocardial Na+/K+ ATPase; its role in CA will be discussed in the section on AF under the heading of comorbidities.

Defibrillation and CRT

Ventricular arrhythmias often represent the terminal events for patients with CA, especially those with AL-CA compared to ATTR-CA, with non-sustained ventricular tachycardia prevalence ranging from 5% to 27% and reaching 100% during stem cell transplants.54,55

In the past, it was argued that ICD implantation might be less beneficial for CA patients owing to a higher defibrillation threshold.56 However, it is now known that ICDs can effectively treat sustained ventricular arrhythmias in these patients.57

In the absence of dedicated studies, all consensus documents agree that an ICD should be offered to patients with standard indications for secondary prevention, with the partial exception of the Japanese guidelines, which do not give a class I indication for secondary prevention; this is because of the lack of demonstrated prognostic benefit and the frequency of pulseless electric activity as the ultimate cause of death.4,58

Attitudes toward ICD implantation for primary prevention range from ‘rather generous (primary prophylactic) indication’ (German Cardiac Society position statement) to the ‘usually not recommended’ (ESC position statement).35,59 The general consensus is that ICD implantation should be avoided in patients with a life expectancy of <1 year.4

In CA patients, despite the high prevalence of LV dysfunction and conduction disturbances, the potential of cardiac resynchronisation therapy (CRT) to promote cardiac remodelling and improve survival has been scarcely explored and all consensus documents refer to the recommendations by corresponding national and international societies.4

The ESC statement is the only one recommending that CRT be considered in patients requiring pacemaker (PM) implantation if the paced burden is predicted to be high; this is likely based on the finding that a higher right ventricular pacing burden is associated with deleterious remodelling and congestive HF in patients with ATTR-CA, while biventricular pacing is associated with improvements in LVEF, New York Heart Association (NYHA) class and degree of mitral regurgitation.35,60 Nonetheless, indications for CRT have been established in patients with non-amyloidotic HF, which warrants further investigations in the specific setting of CA.

In a small study by Donnellan et al., 30 patients with ATTR-CA who underwent CRT implantation were matched based on age, sex, LVEF, NYHA functional class and ATTR-CA stage with 30 ATTR-CA patients who did not receive a CRT device.61 CRT implantation was not only significantly associated with improved LVEF and NYHA class, but also associated with improved survival (HR 0.39; 95% CI [0.21–0.74]; p=0.003).61

Nonetheless, a small multicentre retrospective French study has demonstrated that CA patients seem to have a lower rate of CRT response (absolute delta LVEF ≥10%) and, consequently, a worse cardiovascular prognosis after CRT implantation compared to propensity-matched dilated cardiomyopathy patients.62

Mechanical Circulatory Support and Heart Transplantation

A small LV cavity size and restrictive physiology make CA patients poor candidates to LV assist device implantation.63 Retrospective studies suggest that intra-aortic balloon pumps may be viable as a bridge to heart transplantation (HT) or total artificial heart implantation.64

HT remains a viable option for individuals with ATTRv—either as a standalone procedure or in conjunction with liver transplantation—as well as for selected patients aged <65 years with ATTRwt-CA and certain cases of AL-CA.

For ATTRv-CA patients, a multidisciplinary approach involving cardiologists, hepatologists and neurologists is recommended to evaluate the necessity of combined heart and liver transplantation, as outlined in the 2016 International Society for Heart and Lung Transplantation guidelines (class IIA; level of evidence B).65 Stanford’s HT evaluation guidelines can provide additional guidance in selecting HT candidates.66

In cases of AL-CA, HT is typically considered only after effective chemotherapy has controlled the underlying haematologic disorder; if disease-specific treatments are contraindicated because of HF, early planning for autologous stem cell transplantation is advised. Severe extracardiac amyloid organ dysfunction is generally a contraindication for HT (class IIA; level of recommendation B).65

Guidance on disease-modifying therapies post-transplantation, including in cases involving combined heart and liver transplants or domino transplants, remains unaddressed.

Comorbidities

AF

AF is a prevalent arrhythmia in patients with CA with a mean prevalence of 15% that reaches 40% in ATTRwt-CA.67 It often exacerbates symptoms and complicates disease management owing to the structural and functional abnormalities characteristic of amyloid infiltration in the atria.

However, no evidence on the prognostic benefit of maintaining sinus rhythm versus controlling the heart rate is available, and the consensus documents do not provide any specific recommendation.4 A pragmatic approach is to pursue a rhythm-control strategy when the atria are not extensively remodelled, i.e., enlarged and dysfunctional.

Among antiarrhythmic drugs, non-dihydropyridine calcium channel blockers (verapamil and diltiazem) should be avoided or used with extreme caution because of the risk of precipitating HF decompensation.4 The Japanese guideline allows the use of these drugs, on a case-by-case basis, in patients with ATTR-CA and preserved EF.

Amiodarone is presented as the first-choice antiarrhythmic drug primarily because of concerns about the other drugs.4 Its adverse effects, particularly during long-term administration, are well known.

Digoxin was traditionally contraindicated in patients with CA because of old case reports reporting toxic effects attributed to the binding of digoxin to amyloid fibrils; this was attributed to the accumulation of digoxin in amyloid deposits, although such accumulation has never been demonstrated.68,69 Recent retrospective cohorts suggest that – at least in AL-CA – digoxin is safe when started at low doses and patients are closely monitored.70

Evidence on pulmonary vein isolation (PVI) for AF is very limited. The success rate in patients with CA seems lower than in the general population (75% at 1 year and 60% at 3 years).71 Only the Japanese guideline provides specific recommendations on PVI, stating that patients with paroxysmal AF without left atrium dilatation or LV hypertrophy (i.e., those without extensively remodelled atria) may be candidates for PVI (Class IIb; level C). Conversely, PVI is contraindicated for patients with AL-CA, poor prognosis, severe left atrium dilatation and LV hypertrophy (Class III, level C).58

Conduction Disturbances

Many patients with CA experience atrioventricular (AV) conduction disturbances owing to amyloid infiltration or compression of the AV node and the bundle of His. The basal segments of the septum are often early sites of amyloid deposition.72 The right atrium is less affected, making sinus node disease less common than AV conduction disturbances.73

Data on the prevalence of AV conduction disturbances in CA are fragmented. In a cohort of 25 patients with AL-CA, 92% had prolonged infra-His conduction times, while 88% had normal sinus node function.74

In a multicentre study of 405 patients (29% AL-CA; 15% ATTRv-CA; 56% ATTRwt-CA) without a PM at baseline, 9% received a PM within 3 years. Factors independently associated with PM implantation included a history of AF (HR 3.80; p=0.002), a prolonged PR interval (HR 1.013; p=0.002) and a QRS duration of >120 ms (HR 4.7; p=0.001). The combined presence of these factors increased the risk of PM implantation sixfold (HR 6.26; 95% CI [1.90–20.60]), while their absence had a negative predictive value of 92% over 6 months.75

Severe Aortic Stenosis

The coexistence of calcific aortic stenosis (AS) and CA increases with age and is not uncommon in the elderly.

A meta-analysis found a median CA prevalence of 8% in patients with severe AS referred for valve replacement; 67% were men, the median age was 84 years and nearly all (98%) had ATTR-CA.6 Identifying CA in patients with AS is challenging because they have overlapping features.76,77

A clinical score (RAISE) that uses LV Remodeling (hypertrophy/diastolic dysfunction), Age, Injury (high-sensitivity troponin T), Systemic involvement (e.g. carpal tunnel syndrome) and Electrical abnormalities (right bundle branch block/low voltages) was developed to predict the presence of AS-CA among patients with AS.78

When CA is diagnosed, AS severity should be assessed per current guidelines, noting that around 50% of CA patients exhibit a paradoxical low-flow, low-gradient AS pattern.76 This may be owing to factors such as severe LV concentric remodelling and impaired diastolic filling.76

Patients with severe AS and CA have similar outcomes to those with lone AS when LV thickness is <16 mm, but have worse prognoses with greater thickness.79

Finally, transcatheter aortic valve replacement (TAVR) should not be withheld in patients with CA since there is evidence that it improves survival versus medical management independent of the presence of CA; moreover, periprocedural complications are similar in patients with and without CA.78 AS-CA can also be predicted by the CT routinely performed prior to TAVR by calculating the extracellular volume, which has demonstrated a strong correlation with the degree of amyloid infiltration, as well as with the amount of accompanying fibrosis.38,80

Conclusion

The nuanced interaction between HF therapies and CA presents a challenging yet critical area for clinical research and practice. Evidence from recent studies offers valuable insights but also raises numerous questions regarding the optimal use of neurohormonal blockade in CA patients, challenging the traditional contraindications of such drugs in this setting.34,36,37,39

It is crucial to recognise that CA often requires supportive therapies to stabilise cardiac function, providing the necessary time for disease-modifying treatments to influence the natural progression of the disease. While certain HF medications, such as low-dose β-blockers and MRAs, may offer survival benefits, their efficacy can vary based on patient-specific factors such as disease severity and tolerance to the medication.

This highlights the urgent need for randomised clinical trials to better understand the potential benefits and risks of neurohormonal blockade in this population. Future research should focus on identifying which patients are most likely to benefit from these treatments and at what doses, ensuring that therapy is both effective and safe.

Effective management also necessitates close collaboration between centres specialising in CA and referring cardiologists to optimise care and ensure timely intervention. In summary, until more data are available, clinicians should be aware that neurohormonal antagonist therapies are generally well tolerated, particularly in patients with ATTR-CA and/or in the early stages of the disease.

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