The Arrhythmic Burden of Cardiac Amyloidosis: A Comprehensive Review.

INTRODUCTION

Amyloidosis is a systemic disorder characterized by the extracellular deposition of structurally anomalous and insoluble proteins. In cardiac amyloidosis (CA), this pathological process involves the interstitial infiltration of the myocardium by amyloid fibrils, inducing direct cellular damage, compromising myocardial distensibility, and significantly elevating passive myocardial stiffness.[ 1 , 2 ] CA represents a primary etiology of restrictive cardiomyopathy, manifesting clinically as a rapid deterioration of ventricular diastolic filling in the absence of ventricular dilation. This infiltrative myocardial pathology is fundamentally attributed to the extracellular deposition of conformationally altered amyloidogenic proteins, specifically immunoglobulin amyloid light chain (AL) amyloidosis or transthyretin (ATTR amyloidosis).[ 1 ] Notable risk factors include plasma cell disorders, chronological aging, and particular genetic predispositions. The pervasive amyloid infiltration critically impairs ventricular diastolic properties, disrupts the cardiac conduction system, and culminates in a trajectory of progressive HF.[ 1 ] The most prevalent forms of systemic amyloidosis are AL and ATTR amyloidosis. ATTR amyloidosis is subcategorized into two types: hereditary (hATTR) caused by gene mutations, and wild-type (ATTRwt), an age-related manifestation of native TTR aggregation.[ 2 ] Systemic amyloidosis prevalence in developed countries has historically been dominated by AL amyloidosis, an immunoglobulin light chain-derived disorder. However, ATTR represents a significant component, presenting as either wtATTR, due to age-related aggregation of normal transthyretin (TTR), or hereditart (hATTR), attributable to over 130 identified TTR genetic variants, with Val122Ile being the most prevalent in the U.S. Less common amyloidosis subtypes include inherited apolipoprotein A-1 and A-4 forms, and restricted atrial amyloidosis, involving atrial natriuretic peptide-derived amyloid deposition.[ 3 ]

The epidemiology of CA reveals a spectrum of prevalence that depends on its underlying etiology. AL amyloidosis, occurring in approximately 10% of multiple myeloma patients, frequently manifests with cardiac involvement in 50%–70% of these cases, contributing to an estimated annual incidence of 1 per 100,000.[ 1 ] AL amyloidosis has equal prevalence in both sexes and typically manifests between the ages of 40 and 80 years.[ 4 ] wtATTR amyloidosis, formerly referred to as senile systemic amyloidosis, is the leading cause of cardiac amyloid deposition. Epidemiological data indicate a prevalence exceeding 10% in individuals over 60 years of age, with a common misdiagnosis as HF with preserved ejection fraction (HFpEF). Notable clinical associations include its presence in at least 10% of patients with aortic stenosis and 10%–15% of adults older than 65 years presenting with HFpEF.[ 1 , 5 ]

Recent epidemiological data indicate a significant increase in the incidence of ATTR-cardiomyopathy diagnoses over the past decade, suggesting that current estimates may substantially undervalue the true prevalence of CA as a cause of HF.[ 6 , 7 ] In addition to their propensity for HF, AL and ATTR cardiomyopathies are frequently complicated by a spectrum of arrhythmias, encompassing atrial fibrillation (AF), other supraventricular tachycardias, and ventricular dysrhythmias, alongside intrinsic conduction system disease.[ 6 ] CA typically presents clinically as HFpEF, resulting in symptoms such as exertional dyspnea and fluid retention.[ 4 , 6 ] Concurrently, a high burden of electrophysiological abnormalities is a hallmark of both AL and ATTR cardiomyopathies. These encompass a broad spectrum of arrhythmias, ranging from conduction system disease manifesting as bradyarrhythmias (e.g., atrioventricular [AV] nodal block) to life-threatening tachyarrhythmias (e.g., AF, ventricular arrhythmias).[ 7 ] The differential prevalence of specific arrhythmias, such as the increased incidence of conduction defects and atrial arrhythmias in ATTR amyloidosis, may be attributable to differences in disease progression and patient survival.[ 6 , 7 ]

The objective of this review is to provide a comprehensive analysis of arrhythmias in CA, encompassing the electrophysiological consequences of amyloid infiltration and myocardial remodeling. It aims to delineate distinct arrhythmic patterns based on amyloid subtype (AL, ATTR) while also evaluating diagnostic modalities, risk assessment tools, and therapeutic interventions to optimize clinical care and research in CA-related arrhythmias.

SEARCH STRATEGY

We included peer-reviewed original research articles and review papers that employed diverse clinical, electrophysiological, and translational methodologies. The “English” language filter was applied using the Filter section. A structured literature search was performed using the MeSH keywords “cardiac amyloidosis,” “arrhythmias,” “atrial fibrillation,” “conduction system disease,” “ventricular arrhythmias,” and “electrophysiology,” across multiple electronic databases including Google Scholar, PubMed, Scopus, EMBASE, Wiley Blackwell, SpringerLink, and Web of Science. The study selection process and search strategy are graphically illustrated in Figure 1 .

PATHOPHYSIOLOGY OF ARRHYTHMIAS IN CARDIAC AMYLOIDOSIS

CA, regardless of etiology, is characterized by diffuse extracellular amyloid deposition involving the myocardium, conduction system, and valves. This deposition increases biventricular wall thickness and stiffness, producing a restrictive cardiomyopathy phenotype. Atrial infiltration promotes AF, electromechanical dissociation (EMD), and thromboembolism, even in sinus rhythm. In AL amyloidosis, microvascular involvement of coronary arterioles may precipitate angina or myocardial infarction. Atrial dysfunction and thrombus formation remain key contributors to cardioembolic stroke risk.[ 4 , 8 ] Positron emission tomography (PET) studies reveal abnormal coronary flow reserve in conjunction with microvascular amyloid.[ 9 , 10 ] In AL-CA, direct light chain cardiotoxicity further exacerbates myocardial injury through oxidative stress and cellular dysfunction. Thus, AL-CA pathophysiology reflects a dual mechanism of restrictive infiltration and direct cardiotoxicity [ Table 1 and Figure 2 ].[ 4 , 7 ]

Amyloid deposition and electrical conduction

Conduction system disease in CA results from amyloid infiltration that disrupts myocardial architecture and electrical impulse propagation. In AL amyloidosis, light chain–mediated cytotoxicity further contributes to conduction abnormalities and diastolic dysfunction.[ 17 ]

Beyond its role in myocardial dysfunction, CA significantly increases the propensity for cardiac arrhythmias, including, but not limited to, AF, supraventricular tachycardias, ventricular arrhythmias, and intrinsic conduction system pathologies. Amyloid-related myocardial thickening and fibrosis create a heterogeneous arrhythmogenic substrate. Specifically, atrial amyloid infiltration contributes to myocardial fibrosis and structural remodeling, thereby increasing susceptibility to AF.[ 18 ] This ongoing amyloid deposition within atrial tissue directly compromises homogeneous electrical conduction. In contrast, the direct cytotoxic effects of amyloid fibrils on cardiomyocytes, characterized by fibrosis and oxidative stress, further promote AF pathogenesis. Amyloid deposits exert an infiltrative influence on myocardial conduction tissues, disrupting their conventional architectural integrity.[ 18 , 19 ] This infiltration manifests as various conduction abnormalities: sinoatrial (SA) node involvement can lead to sinus bradycardia, sinus arrest, or SA block; AV node involvement can result in various degrees of AV block, from first-degree to complete heart block; and ventricular amyloid deposition can induce intraventricular conduction delays, thereby perturbing coordinated ventricular contraction.[ 18 ] Clinically, conduction disease may manifest as dizziness, syncope, or palpitations, with characteristic electrocardiography (ECG) findings including prolonged PR intervals, AF, or complete heart block.[ 18 ]

Structural remodeling (atrial and ventricular remodeling, fibrosis)

Clinically significant atrial pathology arises from a multifaceted process known as atrial remodeling, which involves structural, architectural, contractile, and electrophysiological adaptations of the atrial tissue. This process is comprehensively described by three interconnected forms of remodeling, such as structural remodeling, electrical remodeling, and functional remodeling [ Figure 3 ].[ 20 , 21 ] Structural remodeling, marked by atrial enlargement due to alterations in cardiomyocytes and the interstitium; electrical remodeling, involving shortened refractory periods and reduced conduction velocity from diminished L-type Ca 2 ⁺ and Na⁺ currents; and functional remodeling, reflected by contractile dysfunction from persistent L-type Ca 2 ⁺ current suppression, collectively contribute to the maintenance of AF.[ 21 ]

The maintenance or recurrence of AF is closely associated with structural atrial remodeling, a process encompassing atrial enlargement and fibrotic changes. Structural atrial remodeling, encompassing atrial enlargement and interstitial fibrosis, constitutes a fundamental substrate for the initiation and perpetuation of AF.[ 22 ] This stretch precipitates the release of various signaling molecules from diverse cardiac cells, leading to atrial myocyte hypertrophy and fibrosis under pathological conditions. The specific array of released factors, including ANP, angiotensin II, endothelin-1, transforming growth factor-β, and inflammatory cytokines, engages intricate signaling cascades that collectively augment susceptibility to AF.[ 21 , 22 , 23 ] Furthermore, AF compromises both atrial contractile function and electrical conduction, thereby increasing AF vulnerability. The resultant enlarged, fibrotic, and noncompliant left atrium (LA) creates a prothrombotic milieu due to blood stasis.[ 22 , 23 ] Clinically and pathologically, Myocardial infarction triggers a biphasic ventricular remodeling process: an early phase (<72 h) of infarct expansion and mechanical instability, followed by a late phase (>72 h) marked by ventricular dilatation, structural distortion, and compensatory hypertrophy. Persistent wall stress sustains maladaptive remodeling, leading to chamber enlargement, scar extension, and contractile reduction.[ 24 ]

TYPES OF ARRHYTHMIAS IN CARDIAC AMYLOIDOSIS

Dysfunction of the cardiac conduction system, secondary to amyloid infiltration, results in a diverse array of arrhythmias in patients with amyloidosis. These encompass bradyarrhythmic patterns, supraventricular arrhythmias (with atrial tachyarrhythmias being notably prevalent), ventricular ectopy and tachycardia, varying severities of AV conduction block, and a heightened susceptibility to sudden cardiac death (SCD) as depicted in Table 2 .[ 25 ]

Atrial arrhythmias

AF constitutes the most frequently sustained supraventricular tachyarrhythmia detected in individuals with CA, a form of restrictive cardiomyopathy that is established as being linked to the cardiac deposition of pathological amyloid protein aggregates. Epidemiological data indicate a markedly higher incidence of AF in TTR-derived CA compared to the light-chain variant.[ 30 ] The high prevalence of AF in CA is attributed to significant structural and electrical remodeling of the LA resulting from extensive amyloid protein deposition. This infiltration results in atrial fibrosis and EMD, leading to chronic LA pressure elevation, dilation, and subsequent dysfunction. Electrophysiological assessment using LA voltage mapping confirms a severe arrhythmogenic substrate, with significantly lower voltages than non-amyloid AF patients.[ 31 ] AF is a hallmark of CA, being present in 30%–70% of patients at initial diagnosis, and reaching near-universal prevalence (up to 100%) in advanced-stage ATTR amyloidosis.[ 31 , 32 ] This concurrence carries a poor prognosis, as AF in the context of CA confers a 2.5-fold increased risk of stroke compared to non-CA patients, with such thromboembolic events being 2.5 times more frequently fatal. The underlying pathophysiology of CA-related AF is unique, stemming from a synergistic combination of amyloid protein deposition, atrial fibrotic remodeling, electromechanical uncoupling, and autonomic dysregulation.[ 32 ]

In addition to AF, a number of other atrial arrhythmias are also noted in CA patients, showing the widespread atrial remodeling due to amyloid infiltration. Atrial flutter (AFL), (both typical cavotricuspid isthmus-dependent flutter and atypical macroreentrant circuits) can also be found in the range of 5%–15% of CA patients, and commonly exists along with or alternating with AF.[ 33 ] Focal atrial tachycardia (AT) is seen less frequently but usually develops due to foci of atrial fibrosis and conduction heterogeneity formed by the deposition of amyloid. In more progressive disease, a more extreme involvement of the atria can result in atrial standstill, which is a rare but very characteristic arrhythmic abnormality that is seen when there is no electrical or mechanical activity in the atria despite intact conduction in the ventricles.[ 34 , 35 ] The pathophysiological basis of the development of these atrial arrhythmias is similar to that of AF. Gradual amyloid deposition within the atrial myocardium causes structural remodelling, dilation of atria, and widespread interstitial fibrosis, thus causing decreased conduction velocity and inhomogenous electrical propagation. This electrophysiological instability encourages reentrant circuits (in the case of atrial flutter) as well as focal automatic or triggered activity (in the case of AT). Besides, the EMD and atrial contractile dysfunction also have a role in thromboembolic risk despite no persistent AF. These arrhythmias in combination indicate a progressive myopathy of the atria, typical of CA, and the need to monitor rhythm in detail in these patients.[ 36 ]

Ventricular arrhythmias

In the context of cardiac AL amyloidosis, ventricular arrhythmias represent a prevalent electrical disturbance, often leading to a rapid decline in hemodynamic stability following the establishment of HF. Conversely, ventricular tachycardia (VT) constitutes the second most commonly observed rhythm disorder in CA.[ 37 ] VAs in CA are caused by multifactorial pathophysiology comprising diffuse amyloid infiltration resulting in myocardial fibrosis and disorganization, electrophysiological remodeling with dysfunction of ion channels, microvascular ischemia, and involvement of the autonomic nervous system, unlike scar-related arrhythmias in ischemic or dilated cardiomyopathies that are patchy and diffuse and have foci of myocardial substrate.[ 31 , 38 , 39 ] VAs in CA vary between common premature ventricular complexes (PVCs) and nonsustained VT (NSVT), which is observed in about 20%–30% of patients and is an indicator of electrical instability, and less frequent but with a higher prognosis sustained VT 5%–15%) and VF, the latter being the arrhythmia most associated with SCD.[ 38 ] Interestingly, AL amyloidosis patients have a greater incidence of NSVT (27% vs. ATTR 18%), and CA-related VAs are often polymorphic and multifocal (reflecting the complex substrate of the disease). The presence of VAs load is associated with the progression of left ventricular wall thickness, biomarkers (NT-proB-type natriuretic peptide [BNP], troponin), and a high amyloid stage.[ 40 ] VAs are also associated with a highly important risk of SCD. NSVT doubles or triples this risk, whereas sustained VT and VF have already shown the ability to predict a median life span of <6 months in untreated patients.[ 41 ] Furthermore, micro- and macro-vascular obstruction due to amyloid deposition induces myocardial ischemia, evidenced by regional wall motion abnormalities on advanced imaging like cardiovascular magnetic resonance (CMR).[ 38 ] The prognostic assessment for VT in the CA required several key diagnostic modalities. CMR imaging plays an increasingly important role, particularly in demonstrating LGE, which is typically distributed in a global subendocardial pattern and correlates with myocardial fibrosis and arrhythmogenic substrate.[ 38 , 42 ] Standard echocardiographic indices reflecting advanced structural heart disease, such as increased left ventricular internal dimension in systole and reduced left ventricular ejection fraction (LVEF), are also established correlates of VT risk.[ 38 ]

Conduction disturbances

In pathological states, impairments arise from either aberrant impulse generation or anomalous propagation throughout this system, encompassing the SA, AV, and bundle branches. Specific clinical entities within this spectrum include sick sinus syndrome, AV block, bundle branch blocks, and a range of ion channel defects [ Figure 4 ].[ 43 , 44 ]

Conduction abnormalities are a hallmark and prognostically significant complication of CA, affecting multiple levels of the cardiac conduction system, including the sinus node, AV node, and the distal His–Purkinje network. These abnormalities occur due to progressive amyloid infiltration, interstitial fibrosis, and disruption of the vascular supply to conduction tissues.[ 45 ] Sinus node dysfunction is commonly observed and may present as sinus bradycardia, sinus pauses, or sinoatrial block, with reported prevalence ranging from approximately 10%–30% in patients with CA.[ 27 ] These manifestations arise from amyloid infiltration and fibrotic remodeling of the sinoatrial node and its arterial supply, often leading to symptomatic bradyarrhythmias and syncope.[ 27 , 46 ] AV conduction disturbances are also frequent, with first-degree AV block reported in nearly 15%–40% of patients, while higher-degree AV blocks (second- or third-degree) occur in approximately 10%–20% of cases and often necessitate pacemaker implantation.[ 47 ] These abnormalities reflect progressive amyloid infiltration and fibrosis affecting the AV node and surrounding conduction tissue.[ 18 ] Involvement of the distal His–Purkinje system may result in intraventricular conduction delays, including bundle branch blocks. Left bundle branch block (LBBB) has been reported in approximately 20%–35% of patients, whereas right bundle branch block occurs in roughly 10%–15%, reflecting extensive infiltration and fibrosis of ventricular conduction pathways.[ 48 ] Electrocardiographic findings frequently include low-voltage QRS complexes in limb leads combined with QRS prolongation, creating a characteristic discordance between low ECG voltage and increased ventricular wall thickness observed on echocardiography. The prevalence and severity of conduction abnormalities may vary according to the amyloidosis subtype.[ 49 ] AL amyloidosis often demonstrates a higher incidence of conduction disease due to its more rapid and diffuse myocardial infiltration compared with ATTR.[ 50 ] Clinically, conduction system disease contributes significantly to morbidity, with pacemaker implantation required in approximately 15%–30% of patients with CA due to symptomatic bradyarrhythmias or advanced AV block. Because AV block is a recognized predictor of adverse outcomes, including sudden mortality, in CA, meticulous electrophysiological monitoring and prompt intervention via permanent pacing are essential.[ 18 ] However, device therapy addresses only the electrical manifestations of the disease and does not halt the underlying amyloid-mediated myocardial degeneration, and patients may continue to experience progressive heart failure and arrhythmic complications.[ 51 ]

Conduction abnormalities are a common and prognostically significant complication of CA, frequently documented in ATTR amyloidosis. The observed abnormalities encompass a broad spectrum, including SA node dysfunction, various degrees of AV block, and intraventricular conduction delays (e.g., bundle branch block). A proposed pathophysiological mechanism, particularly relevant in AL amyloidosis, involves perivascular amyloid deposition leading to myocardial ischemia and subsequent conduction system fibrosis via impaired vasoactive function. These disturbances are frequently documented in the ATTR (transthyretin) amyloidosis phenotype.[ 45 ] In addition, sinus node dysfunction, including episodes of sinus arrest and marked sinus bradycardia, is a well-recognized feature of CA. The putative mechanism involves the infiltration of amyloid protein, followed by fibrotic restructuring of the SA node and its blood supply, a finding that can sometimes precede overt ECG alterations. Repolarization abnormalities, notably ST-T segment changes, are prevalent. The identification of T-wave inversion mandates an aggressive diagnostic imaging workup, given its potential as an indicator of CA.[ 52 ] The deterioration of both the sinus node and AV conduction is a common sequela of advanced CA. Because AV block is a recognized predictor of adverse outcomes, including sudden mortality, in CA, meticulous electrophysiological monitoring and prompt intervention via permanent pacing are essential.[ 45 ]

ARRHYTHMIA PATTERNS BY AMYLOIDOSIS SUBTYPE

CA encompasses a spectrum of arrhythmic manifestations that differ substantially by amyloid subtype. Notably, AL and ATTR amyloidosis represent the predominant forms impacting myocardial function. While AF is a ubiquitous arrhythmia in both AL and ATTR-related CA, its incidence is markedly elevated in ATTR, particularly the ATTRwt. In contrast, AL-CA is characterized by a higher burden of ventricular arrhythmias, EMD, and SCD in earlier disease stages, reflecting aggressive myocardial toxicity and rapid hemodynamic deterioration. These two amyloidosis subtypes are characterized by divergent pathophysiological mechanisms, clinical presentations, prognostic implications, and therapeutic requirements, necessitating subtype-specific management strategies.[ 7 ]

Amyloid light chain amyloidosis

AL represents an uncommon, multiform disease with an epidemiological burden of approximately 8–12 new diagnoses per million person-years. This intricate and frequently fatal proteopathy is mechanistically linked to the misfolding and subsequent pathological deposition of monoclonal immunoglobulin light chain-derived amyloid fibrils within diverse somatic tissues and viscera. The accumulation of these amyloid aggregates and the circulating burden of free light chains compromise tissue ultrastructure and physiological homeostasis, leading to severe organ dysfunction and high short-term mortality.[ 53 ]

Cardiac involvement in AL amyloidosis, present in 50% of cases, spans a spectrum from minimal to severe. The pathology is characterized by diffuse, extracellular amyloid fibril deposition, impacting the myocardium, valvular structures, and the conduction system. This infiltration results in a restrictive phenotype, characterized by thickened, non-dilated ventricles, severe diastolic dysfunction, and elevated filling pressures, leading to biatrial dilation despite atrial wall thickening. Resultant atrial tachyarrhythmias, mechanical dysfunction, and thrombus formation are significant precursors to cardioembolic cerebrovascular accidents.[ 4 ] In addition, cardiac dysfunction results from multiple pathogenic mechanisms. In AL amyloidosis, myocardial infiltration by light chain fibrils impairs tissue integrity and disrupts cell–cell coupling, promoting cardiomyocyte injury and higher early mortality. Furthermore, LC monomers exert direct cytotoxicity by inducing oxidative stress and interacting with metabolic and cell viability proteins, leading to pronounced myocardial toxicity. In contrast, ATTR amyloidosis typically features slower fibril deposition with less direct cytotoxicity, resulting in a more indolent progression and a lower immediate risk of arrhythmic death, although conduction system disease and atrial arrhythmias remain clinically significant.[ 4 , 54 ] This toxic environment promotes cardiac stress signaling, evidenced by p38 MAPK-mediated upregulation of BNP.[ 54 ] Clinically, this combination of infiltrative and toxic injury translates into a high prevalence of ventricular ectopy, non-sustained and sustained VT, EMD, and bradyarrhythmias, which often manifest earlier and are more malignant than in ATTR-CA.

The diagnosis of immunoglobulin AL rarely occurs during the pre-symptomatic phase. The heterogeneous and non-specific clinical presentation, which often includes findings like heart failure with neuropathy, nephrotic syndrome, hepatomegaly, periorbital purpura, and macroglossia, is indicative of significant, advanced organ pathology rather than early-stage disease. It is pertinent to note that concomitant neuropathy and cardiomyopathy are also prevalent features of hereditary (ATTRm) transthyretin amyloidosis.[ 54 ] The urgency of early detection for AL-CA stems from its deleterious effect, which typically involves rapid decline into heart failure, SCD risk from arrhythmias, and high untreated mortality. In contrast to AL-CA, ATTR-CA is driven by misfolded transthyretin (TTR) deposition without direct light chain–mediated cytotoxicity, leading to more indolent myocardial remodeling and a different arrhythmic profile. Relative to the AL form, ATTR cardiac involvement demonstrates slower disease progression (particularly wtATTR), which correlates with a better long-term survival outlook in the absence of specific therapy.[ 7 ]

Cardiac amyloid light chain amyloidosis

Cardiac AL amyloidosis, affecting the majority of AL amyloidosis patients (~80%), is a highly lethal complication, significantly shortening survival (median <1 year). This cardiac involvement manifests as heart failure. Pathophysiologically, light chains may induce cardiac stress responses, potentially involving p38 MAPK-mediated BNP expression. While sudden death (SD) is often due to pulseless electrical activity (PEA) or ventricular arrhythmias, alternative mechanisms include thromboembolism, bradyarrhythmias, conduction system disease, and autonomic dysfunction. Transthyretin amyloidosis (ATTRm or ATTRwt) represents an alternative etiology for CA.[ 54 ] Compared with ATTR-CA, AL-CA patients are more likely to present with VT, EMD, and SD at lower degrees of structural remodelling, underscoring a lower arrhythmic threshold and more unstable hemodynamics.

The hallmark of AL-CA is the deposition of amyloid fibrils derived from immunoglobulin light chains within the cardiac extracellular matrix, leading to symmetrical thickening of the ventricular myocardium. The characteristic pattern of amyloid deposition is diffuse and subendocardial, with localization interstitially surrounding cardiomyocytes and within the walls of intramural coronary arteries.[ 54 , 55 , 56 ] This infiltration commonly extends to the cardiac valves, resulting in valvular thickening and subsequent regurgitation. Patients may also manifest with minimal pericardial effusions and ischemic symptoms arising from intrinsic coronary artery involvement, even in the presence of patent epicardial vessels. The increased myocardial stiffness imparted by amyloid infiltration primarily leads to diastolic dysfunction and impaired ventricular filling, with progressive disease culminating in systolic contractile impairment.[ 56 , 57 ] Cardiac compromise represents the primary determinant of survival, with heart failure and arrhythmias responsible for approximately 75% of mortalities. The untreated natural history of AL-CA is severe, characterized by a median survival of <12 months. At the same time, cardiac involvement is a feature in over 90% of systemic cases; approximately 5% of patients present with cardiac-only disease. Amyloid infiltration of all cardiac components leads to ventricular hypertrophy, impaired relaxation, and the development of restrictive ventricular physiology. Amyloid deposition within the cardiac electrical conduction system frequently predisposes to the development of dysrhythmias.[ 56 , 58 , 59 ] From a clinical management perspective, conventional heart failure and arrhythmia therapies (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, and negative inotropes) are often poorly tolerated in AL-CA because of low blood pressure, small stroke volume, and autonomic dysfunction, necessitating cautious dosing and early consideration of chemotherapy-based plasma cell-directed therapy to modify arrhythmic risk.

ATTR (Transthyretin) amyloidosis

TTR is a 55 kDa protein made up of 127 amino acid subunits with significant β-sheet secondary structure. It is primarily produced in the liver and choroid plexus, playing a crucial role in transporting thyroxine and holo-retinol-binding protein in biological fluids. Its misfolding and extracellular deposition as amyloid fibrils (ATTR amyloidosis), encompassing both wild-type and hereditary variants, leads to systemic organ pathology.[ 60 ] In contrast, ATTR amyloidosis, including ATTRwt and hATTR forms, exhibits slower disease progression with predominant atrial involvement. Chronic extracellular deposition of misfolded transthyretin fibrils leads to atrial structural remodeling, left atrial dilation, and electromechanical uncoupling, predisposing primarily to AF rather than life-threatening ventricular arrhythmias.[ 61 , 62 ] While conduction system disease can occur, it is generally less severe than in AL-CA. Prognostically, ATTR-CA has a more indolent course, with median survival of 4–6 years from symptom onset for untreated patients, although hATTR variants with cardiomyopathy-predominant phenotypes may carry a higher risk.[ 62 ]

Wild-type transthyretin amyloid cardiomyopathy

ATTRwt is a lethal, sporadic proteinopathy characterized by the extracellular accumulation of organized amyloid fibrils, derived from wild-type TTR (formerly prealbumin), within cardiac tissue. This condition is frequently identified in elderly individuals presenting with cardiomyopathy and characteristic heart failure symptomatology.[ 63 , 64 ] A reported median survival of 80 years postsymptom onset suggests ATTRwt may be an underdiagnosed etiology of heart failure, particularly among older Caucasian males exhibiting diastolic dysfunction. Diagnostic confirmation of ATTRwt presents challenges, as endomyocardial biopsy, the gold standard for amyloid detection, carries substantial procedural risks in geriatric patients. Furthermore, in the absence of histopathological confirmation, disease identification relies on the judicious interpretation of echocardiographic, cardiac magnetic resonance, or nuclear scintigraphic findings. Circulating biomarkers indicative of myocardial injury, such as cardiac troponin I (cTn-I) and BNP, are utilized to support an ATTRwt diagnosis and monitor disease progression.[ 63 ] Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) constitutes an underdiagnosed cause of heart failure, driven by the progressive extracellular deposition of misfolded wild-type transthyretin (TTRwt) protein.[ 61 ] This pathological process involves the generation of insoluble, toxic protein aggregates through concurrent or alternative misfolding, which subsequently organize into fibrillar β-sheet bundles within tissues. Clinical signs and symptoms result from amyloid fibril-induced disruption of tissue structural integrity and physiological function, with cardiac involvement as the predominant clinical phenotype.[ 61 ] Unlike AL-CA, ATTRwt-CA is strongly associated with atrial remodeling and a very high prevalence of AF and other atrial tachyarrhythmias, often exceeding 60%–70% and approaching near-universal AF in advanced stages. The development of AF is intrinsically linked to adverse clinical trajectories and elevated requirements for acute hospital-based management. Crucially, the susceptibility to intracardiac thrombus burden and thromboembolic sequelae is notably high in CA patients with AF, a vulnerability observed even in situ of anticoagulation therapy.[ 62 ] Conduction system disease (e.g. AV block, bundle branch block) is particularly common in ATTR-CA, resulting in a distinct bradyarrhythmic phenotype that often necessitates early permanent pacemaker (PPM) implantation.

Hereditary transthyretin amyloidosis

hATTR is a severe, genetically heterogeneous, multisystem disorder. It is characterized by the extracellular deposition of amyloid fibrils, resulting from mutations in the TTR gene. While historically categorized as polyneuropathy-dominant (hATTR-PN, or Familial Amyloid Polyneuropathy) or cardiomyopathy-dominant (hATTR-CM, or Familial Amyloid Cardiomyopathy), most patients experience both neurological and cardiac manifestations.[ 65 , 66 ] The underlying cause of hATTR is attributed to pathogenic mutations within the TTR gene, located on chromosome 18.[ 67 , 68 ] The molecular mechanism involves the destabilization of the TTR tetramer by these mutations, leading to its dissociation into monomers.[ 65 , 67 ] These monomers then undergo aberrant folding and aggregate into amyloid fibrils, which deposit in extracellular spaces, causing diffuse multisystemic dysfunction.[ 65 ] Due to the significant prevalence of pathogenic TTR gene mutations, hereditary ATTR amyloidosis constitutes the primary familial etiology for amyloid cardiomyopathy, potentially ranking as the most common cardiac amyloid subtype. The disease phenotype, which typically appears after the age of 40, is determined by the precise location of the amino acid variant within the TTR sequence.[ 65 , 69 ] Cardiac deposition of amyloid fibrils, regardless of TTR genotype (hereditary or wild-type), induces left ventricular wall hypertrophy and subsequent functional perturbations. These changes result in a pattern of restrictive cardiomyopathy, characterized by impaired left ventricular filling (diastolic dysfunction) and associated alterations in contractile performance (systolic function).[ 69 ] Clinically, hATTR-CM shares the predominant atrial arrhythmia and conduction disease phenotype observed in ATTRwt-CA, but often in younger patients with coexistent autonomic neuropathy, leading to complex interactions between orthostatic hypotension, bradyarrhythmias, and AF management. From a therapeutic standpoint, ATTR-CA uniquely benefits from TTR-targeted disease-modifying therapies (Tafamidis, gene silencers, and emerging TTR stabilizers), which may stabilize or slow arrhythmic progression, a strategy not available for AL-CA, where clone-directed chemotherapy and hematologic response remain central to improving arrhythmic outcomes.

Clinical implications

AL and ATTR amyloidosis are distinct arrhythmic conditions, not only variations of the same disease. AL amyloidosis tends to cause early, malignant arrhythmias due to myocardial toxicity and progresses rapidly. In contrast, ATTR amyloidosis primarily involves atrial involvement and gradually progressive bradyarrhythmias. These differences impact prognosis, device therapy choices, anticoagulation strategies, and the prioritization of disease-modifying treatments, emphasizing the importance of tailored arrhythmia management for each subtype.

DIAGNOSTIC CONSIDERATIONS

The differential diagnosis of hypertrophic cardiomyopathy necessitates careful consideration of the most prevalent genetic and nongenetic conditions, in addition to excluding readily identifiable causes such as chronic hypertension and aortic stenosis. Crucially, the presence of aortic stenosis and clonal immunoglobulin abnormalities does not preclude a diagnosis of ATTR-CA. Optimal typing of amyloidosis, particularly AL amyloidosis, is achieved through the integrated use of bone scintigraphy and comprehensive monoclonal protein assays.[ 70 ]

Electrocardiography findings

The foundational ECG findings in CA, first delineated in the 1950s, included hallmark signs such as low voltage in peripheral leads, poor R-wave progression in precordial leads, and a pseudonecrosis appearance. QRS axis deviations, AF, and AV conduction deficits were also part of this initial characterization. A direct relationship exists between amyloid burden and both the magnitude of ECG alterations and the prevalence of arrhythmias. The pseudonecrosis pattern, identified by Q waves of at least 1 mV in a minimum of two contiguous leads without a history of ischemic heart disease and/or akinetic or dyskinetic left ventricular segments, is evident in up to 70% of CA patients, exhibiting comparable frequency in ATTR and AL amyloidosis.[ 39 , 71 ] Low QRS voltage on ECG serves as a significant diagnostic marker for CA, identified in a substantial proportion (25%–90%) of affected individuals, particularly those with AL amyloidosis. The variability in reported prevalence underscores the impact of diverse “low voltage” definitions (e.g., Sokolow-Lyon index ≤15 mV, peripheral lead voltage ≤5 mV, or global lead voltage ≤5 mV peripheral and ≤10 mV precordial). Critically, the typical predictors of QRS voltage in healthy individuals, such as left ventricular mass and demographic factors, are uncoupled in CA due to amyloid infiltration, which causes wall thickening but impedes electrical conduction. Therefore, a disproportionate relationship between elevated left ventricular mass and attenuated QRS voltage should raise a strong suspicion for CA.[ 39 ]

Rhythm monitoring

Rhythm monitoring in CA is crucial due to the high prevalence of arrhythmias, which significantly impact patient morbidity and mortality. A comprehensive approach is employed, as the type and frequency of arrhythmias vary depending on the amyloid subtype (AL vs. ATTR) and the disease stage.[ 31 ] Arrhythmias, including AF, atrial flutter (AFL), conduction system disorders (such as heart blocks), and ventricular arrhythmias, are common in a substantial number of CA patients, with some studies indicating rates as high as 88%. The presence of arrhythmias correlates with markedly increased in-hospital mortality, prolonged hospital stays, and more frequent hospitalizations due to heart failure exacerbations. AF and AFL in CA patients pose an especially high risk of intracardiac thrombus formation and stroke, often independent of traditional risk scores like CHA2DS2-VASc. This underscored the importance of routine and continuous monitoring to facilitate prompt and appropriate anticoagulation therapy. Ventricular arrhythmias and advanced conduction blocks are key contributors to SCD in CA patients. Although the mechanisms of SCD can be complex, often involving EMD in advanced stages, monitoring helps identify patients at risk who may benefit from implantable cardioverter-defibrillators (ICDs) or pacemaker placement. Arrhythmias in CA typically cause hemodynamic instability because the stiff, amyloid-infiltrated heart depends on a consistent, often faster, heart rate and atrial “kick” to sustain cardiac output. Rhythm monitoring guides therapy decisions, as many conventional rate-control medications (such as beta-blockers and calcium channel blockers) are poorly tolerated and may induce hypotension or worsening heart failure.[ 6 , 31 ]

Two-dimensional echocardiography

Echocardiography constitutes the most frequently employed non-invasive cardiac imaging modality for the structural and functional assessment of the myocardium. Two-dimensional (2D) echocardiographic examination provides crucial morphological characteristics, including myocardial hypertrophy (e.g., thickened ventricular walls and papillary muscles) and valvular thickening. A highly suggestive, though non-specific, feature is the “granular sparkling” myocardial texture.[ 72 , 73 ] The widespread clinical adoption of echocardiography is driven by its inherent safety profile, high availability, portability, cost-effectiveness, and its capacity to furnish comprehensive hemodynamic and diastolic function data. While transthoracic echocardiography (TTE) is not independently conclusive for definitive subtype diagnosis (e.g., distinguishing between AL amyloidosis and ATTR amyloidosis), it remains a cornerstone in the diagnostic algorithm, prognostic stratification, and long-term therapeutic surveillance of patients presenting with suspected or confirmed CA.[ 72 , 74 ] The 2022 ESC Guidelines on cardio-oncology recognize echocardiography as a Class IB recommendation for the initial diagnostic of CA.[ 74 ]

Two-dimensional echocardiography

For detecting CA, two-dimensional echocardiography is the recommended initial screening test. The presence of the disease is generally associated with abnormal ultrasonic reflectance within the myocardium. Of the various imaging features, left ventricular hypertrophy is the most highly suggestive echocardiographic finding, even though it requires further, specific testing for confirmation.[ 75 ] Two-dimensional echocardiography plays a crucial role in diagnosing CA by revealing typical signs like thickened heart walls, a small left ventricular cavity, biatrial enlargement, and a myocardium with a “granular sparkling” appearance. It also helps distinguish amyloidosis from other conditions, as the findings can mimic hypertrophic cardiomyopathy or hemochromatosis. Key features in CA include reduced global longitudinal strain and relative apical sparing.[ 76 ]

Advanced imaging correlation

Advanced cardiac imaging (ACI) techniques provide superior risk stratification for ventricular arrhythmias and SCD compared to LVEF. CMR with LGE identifies myocardial scar, guiding ICD therapy. PET and single-photon emission computed tomography (CT) evaluate myocardial viability, innervation, and inflammation.[ 77 , 78 ] CT characterizes myocardial fat, implicated in reentrant circuits. These modalities yield quantifiable parameters (e.g., left ventricular mass, volume, and dyssynchrony) reflecting structural, functional, and metabolic alterations that are predictive of arrhythmogenic potential, especially in non-ischemic cardiomyopathy. Integrating ACI data with clinical variables is anticipated to improve prognostication for arrhythmic mortality.[ 77 ]

Cardiovascular magnetic resonance findings

CMR has become the gold standard for assessing ventricular morphology and function. Specifically, cardiac cine MR accurately quantifies myocardial mass, atrial/ventricular architecture, and global cardiac function, including characteristic features of restrictive cardiomyopathy with preserved ejection fraction. Early CA infiltration often manifests as abnormal stroke volume, even when ejection fraction is preserved, likely due to increased myocardial mass reducing end-diastolic ventricular volume.[ 79 , 80 ] While conventional CMR has limitations in evaluating diastolic function, advanced techniques such as tagging, feature tracking, and velocity-encoded MR enable the extraction of strain, strain rate, and torsion, offering novel insights into diastolic mechanics. Furthermore, T1 mapping provides an alternative CMR-based method for diastolic function assessment.[ 80 ] A key advantage of CMR is its unparalleled capacity for “myocardial tissue characterization.” Although non-contrast T1 and T2 signals can differentiate normal from abnormal myocardium, their utility is somewhat restricted. Prior studies have not reported myocardial edema in CA, as evidenced by the absence of T2 signal alterations. The correlation between elevated native myocardial T1 and troponin release or high T2 signal remains unresolved, as noted by Carvalho et al . It is generally accepted that common forms of CA, namely AL and ATTR amyloidosis, exhibit similar CMR phenotypes.[ 79 , 80 ]

Nuclear imaging (bone scintigraphy) correlation

The application of 99 mTc-phosphate bone scintigraphy in CA diagnosis, specifically for transthyretin amyloidosis ATTR-CA, originated from observations in the 1980s. While the precise uptake mechanism is unknown, the technique is highly sensitive.[ 81 ] A landmark 2005 study demonstrated the diagnostic efficacy of 99 mTc-DPD, corroborated by subsequent studies validating other bone tracers. Recent multicenter trials confirm that bone scintigraphy reliably diagnoses cardiac ATTR CA noninvasively.[ 82 ] The current diagnostic algorithm states that in patients without free light chains, a negative 99 mTc-PYP/99 mTc-DPD/99 mTc-HMDP scan largely excludes CA. Conversely, Grade 2/3 cardiac uptake on these scans in the absence of free light chains confirms ATTR CA with >98% specificity/PPV, precluding biopsy. However, for patients with plasma cell dyscrasia, biopsy remains necessary due to potential false positives from mild uptake in other amyloidosis types. The role of these tracers in assessing extra-CA is emerging; 99 mTc-DPD shows characteristic muscle/soft-tissue uptake correlating with amyloid infiltration, and 99 mTc-HMDP can identify pulmonary ATTR uptake, though clinical significance requires further study. Tracer specificity is observed, with 99 mTc-PYP not exhibiting similar skeletal muscle uptake.[ 81 ]

RISK STRATIFICATION

Arrhythmic risk assessment

The assessment of arrhythmic risk in CA requires a subtype-specific and disease-stage-oriented approach rather than reliance on conventional arrhythmia risk models developed for non-infiltrative cardiomyopathies. In CA, ECG interpretation must focus on discordance between increased ventricular wall thickness and low QRS voltage, progressive PR/QRS prolongation, and pseudonecrosis patterns, all of which reflect amyloid infiltration rather than primary channelopathy.[ 83 ] Standardized clinical risk scores, such as the CHA2DS2-VASc for thromboembolic risk in AF and HAS-BLED for bleeding risk in AF, are valuable when applied within their validated scopes. Imaging techniques, including echocardiography, cardiac magnetic resonance imaging (MRI), and CT, are crucial for evaluating LVEF and identifying structural cardiac pathologies. Cardiac MRI with late gadolinium enhancement is specifically recommended for myocardial scar assessment, a significant predictor of SCD and sustained VT.[ 83 ] Invasive electrophysiological studies have limited routine prognostic value in CA but may be selectively considered in unexplained syncope to distinguish conduction disease from ventricular tachyarrhythmias.[ 84 , 85 ] Emerging digital health technologies, including smartphone applications and wearable devices, as well as artificial intelligence, show promise for AF detection.[ 83 ] While Cardiac Troponin T (cTnT) is the primary biomarker for diagnosing myocardial cell injury and is central to acute coronary syndrome assessment, its interpretation necessitates nuanced consideration. Elevated NT-proBNP and hs-TnT form the basis of validated staging systems in AL amyloidosis and provide indirect prognostic insight into arrhythmic and overall mortality risk.[ 83 , 86 ] This manuscript concurrently addresses AF risk assessment in specialized groups, including athletes, heart failure (HF) patients, individuals post-cryptogenic stroke, those with inherited rhythm disorders, and individuals with established AF predisposing factors.[ 86 ] In the context of HF, a meticulous evaluation of AF risk factors is advocated, coupled with remote monitoring or frequent interrogation of implanted cardiac devices to facilitate the timely identification of incident arrhythmias.[ 86 , 87 ]

Sudden death risk

SD in CA differs fundamentally from conventional ischemic or dilated cardiomyopathy, where sustained ventricular tachyarrhythmias are the dominant mechanism. In CA, SD is frequently caused by EMD or PEA, rather than shockable ventricular arrhythmias. This distinction has major therapeutic implications, particularly regarding ICD effectiveness.[ 88 ]

SCD faces substantial challenges, which involve the synergistic convergence of an inherently vulnerable cardiac substrate with acute, transient precipitating factors.[ 89 , 90 ] Markers such as nonsustained VT, syncope, elevated cardiac biomarkers, and extensive LGE may suggest higher risk, but none reliably predict ICD-responsive arrhythmias in CA.[ 90 ]

While the predominant causes of mortality often relate to preexisting conditions, such as congenital cardiomyopathies, coronary anomalies, or genetic arrhythmias in younger individuals, and coronary heart disease in athletes over 35.[ 91 ] In CA, however, the pathophysiology leading to VA and death is multifactorial. In AL amyloidosis, prognosis is often primarily affected by direct toxicity from light chains and swift hemodynamic decline. Conversely, in ATTR amyloidosis, progressive conduction issues and bradyarrhythmias tend to be the main causes of SD.[ 92 ] In patients with CA, SCD is most often attributed to EMD. Nevertheless, both VA and conduction abnormalities are common findings.[ 92 , 93 ] AL-CA carries a significantly elevated risk of SD, which may even serve as the initial clinical manifestation. PEA and ventricular arrhythmias are the most frequent etiologies; other potential causes include thromboembolic events, bradyarrhythmias, and conduction abnormalities stemming from either direct amyloid infiltration or autonomic nervous system dysfunction.[ 93 ]

MANAGEMENT STRATEGIES

The clinical management of cardiac rhythm disorders in CA requires disease-specific consideration due to restrictive physiology, preload dependence, autonomic dysfunction, and progressive conduction system infiltration [ Figure 5 ]. Lifestyle modifications primarily aim to optimize cardiovascular health through dietary adjustments, structured exercise programs, and psychological stress mitigation.[ 94 , 95 ]

Rate and rhythm control in atrial arrhythmias

Rate- and rhythm-control strategies are used to manage atrial arrhythmias, such as AF and AFL, by either regulating the ventricular response or restoring normal sinus rhythm. In the general population, rate control typically aims to maintain a resting heart rate of 60–80 beats per minute using AV nodal blocking agents, including beta-adrenergic antagonists and non-dihydropyridine calcium channel blockers [ Table 3 ].[ 96 ] However, in CA, restrictive ventricular physiology and a relatively fixed stroke volume often require a higher heart rate to maintain adequate cardiac output, making conventional rate-control strategies challenging.[ 100 ] The use of Class I antiarrhythmic agents is not recommended in CA because of structural myocardial disease underlying and increased proarrhythmic risk.[ 95 ] Class II Beta-blockers are poorly tolerated due to autonomic dysfunction and baseline hypotension; even low dosages can trigger fatigue, bradycardia, or cardiogenic shock in severe disease. Class IV (non-dihydropyridine calcium channel blockers) are usually contraindicated because of negative inotropic effect and risk of aggravation of heart failure affecting restrictive cardiomyopathy.[ 95 , 98 , 99 ] In addition, calcium channel blockers may precipitate significant hypotension and conduction disturbances in patients with CA and are therefore generally avoided.[ 100 ] In CA, however, drug selection is constrained by poor tolerance, limited efficacy, and heightened risk of hemodynamic compromise. In AF, rate-control strategies are frequently ineffective or poorly tolerated. Standard agents (e.g., β-blockers and non-dihydropyridine calcium channel blockers) often precipitate hypotension, bradycardia, or heart failure decompensation.[ 101 ] Because of these limitations, rhythm-control strategies are often favored in symptomatic patients, as restoration of AV synchrony may improve ventricular filling and cardiac output. Amiodarone is commonly preferred for its combined rate- and rhythm-control properties and its relative hemodynamic stability. Among antiarrhythmic agents, amiodarone is generally considered the most effective and best-tolerated option for rhythm management in CA.[ 31 ] Low-dose digoxin may be cautiously considered, particularly in heart failure, with close surveillance given its narrow therapeutic index.[ 97 ] Although disease-modifying treatments for ATTR do not directly affect arrhythmia burden; by stabilizing myocardial structure and slowing disease progression, they may indirectly reduce arrhythmia burden. There are promising novel therapies on the horizon that target pathogenic TTR fibril formation, including TTR gene silencers, TTR tetramer stabilizers, oligomer aggregation inhibitors, anti-TTR fiber antibodies, and TTR amyloid degraders (ongoing clinical trials).[ 8 ] Small molecules like Tafamidis and diflunisal act by mimicking the inherent stabilizing conformational change conferred by specific TTR variants, such as T119M (e.g., acoramidis).[ 102 ] Tafamidis is a TTR stabilizer that highly selectively binds to the thyroxine-binding sites, preventing TTR tetramer dissociation into misfolding intermediates. It has shown a survival benefit in ATTR cardiomyopathy (ATTR-CM), as evidenced by the ATTR-ACT trial.[ 103 ]

Beyond TTR stabilizers, the secondary therapeutic approach for ATTR amyloidosis involves TTR gene-silencing agents. siRNAs (patisiran and vutrisiran) and ASOs (inotersen and eplontersen) downregulate hepatic TTR production by inducing the degradation of the TTR mRNA transcript via complementary binding.[ 102 ] Patisiran and inotersen for ATTR-FAP, independent of ATTR-CM, ameliorate cardiac structural and functional parameters.[ 102 , 104 ] In cases where pharmacological therapy fails to achieve adequate rate control, AV nodal ablation followed by PPM implantation may be considered as an alternative strategy.[ 31 ]

Anticoagulation strategy

Anticoagulation in atrial arrhythmias is used mainly to prevent stroke in AF and AFL, although, in CA, traditional risk stratification measures might fail to recognize thromboembolic risk. It is highly recommended that oral anticoagulant treatment should be used to prevent the risk of ischemic stroke or systemic embolism in patients with AF related to CA because such patients are at high intrinsic risk of thromboembolism due to atrial mechanical and amyloid infiltration.[ 96 , 105 ] Unlike in the general AF population, anticoagulation is usually advised in patients with CA and AF regardless of the CHA2DS2-VASc scoreanticoagulation is usually advised in patients with CA and AF, regardless of the CHA2DS2-VASc score, because thromboembolic events have been observed even in patients with low conventional risk scores. This increased risk is ascribed to atrial myopathy, degenerated atrial myocardial contractility, and stagnant blood due to the presence of amyloid in the atrial myocardium.[ 96 , 106 ] HAS-BLED is used to assess modifiable bleeding risks and monitor them, although in patients with CA, it should primarily be used to inform bleeding risk reduction rather than to decide whether to use anticoagulation. DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) should be first-line because they have lower bleeding risks and better-predictable pharmacokinetic profiles than Vitamin K antagonists.[ 96 ]

Controversies in device therapy for cardiac amyloidosis-associated arrhythmias

Device therapy in CA poses unique challenges and remains highly controversial compared to management in non-amyloid populations. Conduction system disease has a high prevalence in CA, mainly due to amyloid infiltration and fibrosis of the AV node and His–Purkinje system, leading to the need for PPMs in many cases. In contrast to the non-amyloid population, in which PPM implantation is consistently successful at alleviating symptomatic bradyarrhythmias, CA patients may undergo swift disease progression characterized by higher pacing dependency and the risk of worsening heart failure due to the development of loss of AV synchrony and right ventricular pacing-induced dyssynchrony.[ 51 ] Abnormal myocardial substrate is a distinct technical challenge in CA, as it often results in high pacing thresholds and low sensing amplitudes at the time of pacemaker implant. The amyloid tissue infiltrate is dense, which can interfere with electrical conduction and reduce capture of pacing stimuli, leading to increased acute and chronic pacing thresholds that may deteriorate over time.[ 1 , 2 ] Finally, low R-wave amplitudes and poor sensing may predispose to undersensing of intrinsic cardiac activity with the risk of inappropriate pacing, loss of AV synchrony, or device dysfunction.[ 6 ] Unlike non-amyloid patients, where thresholds and adequate sensing are consistently reached post-implant at appropriate values, these pacing parameters remain unique in amyloid disease. The incorporation of steroid-eluting leads and diligent intraoperative threshold measurement during implantation have reduced these risks, but often requires frequent device reprogramming and close follow-up.[ 6 ]

ICD therapy in the setting of CA is one of the most controversial aspects of device management [ Tables 4 and 5 ]. Indeed, although all CA patients, especially those who have light chain (AL) amyloidosis or transthyretin (ATTR), are at high risk for ventricular arrhythmias, the underlying mechanisms of SCD in amyloidosis are qualitatively different from cardiomyopathy. SCD is commonly due to EMD or PEA, neither of which is treatable with ICD shocks.[ 114 , 115 ]

Recent studies document these challenges: Maurer et al . reported that in patients with ICDs and advanced CA, only 16% received appropriate shocks, whereas 57% died without having ever received appropriate therapy from their ICD (most commonly due to progressive heart failure or PEA).[ 116 ] Similarly, Bosman et al . reported that appropriate ICD therapies were rare (14.3%)[ 117 ] and long-term mortality remained poor, in particular for patients with AL amyloidosis, with a median post-implant survival of only 14 months. This is also supported by larger studies showing the relative infrequency of ventricular arrhythmias as compared to the progression of heart failure and nonshockable rhythms leading to death.[ 116 ] Moreover, technical problems such as high defibrillation thresholds or low R-wave amplitudes may impair ICD performance, while device-related complications are more common because of the fragile and infiltrated myocardium.[ 6 , 118 ]

Thus, ICDs are typically only indicated for secondary prevention (in patients with documented ventricular arrhythmias) and select primary prevention cases after multidisciplinary discussion, and specifically not for routine therapy in CA.[ 117 , 115 ]

Cardiac resynchronization therapy (CRT) also presents unique issues in CA. Although CRT has been shown to be effective in patients with heart failure who have LBBB or substantial dyssynchrony, it is less clear for CA. Diffuse and restrictive myocardial disease due to amyloid infiltration may reduce the CRT response. The estimated proportion of CA patients receiving device therapy and implanted with CRT devices (CRT-P or CRT-D) based on retrospective data is as high as 13%.[ 119 ] In amyloid populations, response rates would be lower, as highlighted by a multicenter study by Donnellan et al . Only 29% of CA patients with CRT experienced significant improvement in HF symptoms or LVEF at 6 months; response rates in the general population of nonamyloid CRT recipients are 60%–70%.[ 119 , 120 ]

A separate UK study of 30 amyloid patients treated with CRT[ 121 ] showed that only 23% had a favorable echocardiographic response (defined based on either ≥5% absolute increase in LVEF or ≥15% reduction in LV end-systolic volume), whereas the remaining patients experienced little to no clinical nor structural improvement. In addition, due to the fragile, infiltrated myocardium, procedure-related risks associated with CRT implantation at CA are higher compared to ICM, such as lead dislodgement, myocardial perforation, and infection.[ 122 ]

The current clinical decision-making is even more challenging, given the dismal overall prognosis in advanced CA, especially in light-chain amyloidosis, which gives rise to both ethical and cost-effectiveness issues regarding device therapy.[ 119 ] Current recommendations offer limited guidance for device use in amyloidosis, and there is a paucity of rigorous, prospective data to inform therapy.[ 51 , 119 ]

PPM, ICD, and CRT are cornerstone therapies for arrhythmias and heart failure in the general population, but their application to CA must be individualized based on thorough risk-benefit analysis, and further research is needed to clarify many unresolved controversies around these devices to maximize patient outcomes.

Catheter ablation

AF ablation remains a unique challenge in the treatment of CA, with lower long-term success rates and higher recurrence than AF in the non-amyloid population. CA is defined by the deposit of amyloid fibrils into myocardial tissue, which results in progressive stiffening of both the atria and ventricles, electrical modeling, and augmented atrial fibroses. These structural and electrophysiological alterations promote a substrate for arrhythmia, such that AF becomes increasingly persistent as well as less amenable to traditional rhythm-control strategies. In a series of 72 ATTR-CA patients, only 42% of those receiving catheter ablation were free from recurrent arrhythmia after an average of 39 months, with significantly higher success in early stages (64% for Stages I–II vs. 10% for Stage III).[ 123 ] In addition, patients with CA demonstrate significantly increased incidence of AF recurrence and have more complications related to the procedure, including exacerbation of heart failure or bradyarrhythmias requiring pacemaker implantation.[ 123 , 124 ] In contrast, ablation in non-amyloid patients generally demonstrates higher success rates and lower recurrence rates due to the absence of infiltrative pathology.[ 125 , 126 ] Catheter ablation is one of the strategies that can improve mortality and hospitalization in CA if performed in selected cases and through appropriately multidisciplinary management.[ 123 ]

Catheter ablation for ventricular arrhythmias such as premature ventricular contractions (PVCs) and VT in the presence of CA is particularly challenging as well. The diffuse myocardial infiltration and fibrosis form an arrhythmogenic substrate that is more complex than the more focal scar seen in non-amyloid cardiomyopathy. Whereas VT ablation in non-amyloid patients has acute success rates of 70%–80% and 1-year VT recurrence of 20%–40%, the experience for CA patients is lower acute procedural success (46%–67%) and much higher recurrence rates. For instance, Muser et al . reported that only 60% of amyloidosis patients were free of VT at the time of hospital discharge, whereas 80% had developed recurrent VT or died by a median follow-up of 4 months.[ 127 ] In another multicenter study, only 17% of patients with amyloidosis were VT-free at 12 months, compared to >50% of matched non-amyloid controls.[ 7 ] The procedural mortality is also increased in CA, with a reported rate of peri-procedural death up to 17%.[ 127 , 128 ] Report data on PVC ablation in amyloid patients is limited, but suggests both lower efficacy and higher recurrence due to the diffuse infiltration and challenges of detailed mapping. Ablation of both AF and VT in CA is associated with lower success rates, higher recurrence rates, and greater risk than in non-amyloid populations, underscoring the need for endocardial vs epicardial multidisciplinary, individualized care and realistic counseling.

CONCLUSION

CA is a progressively debilitating infiltrative cardiomyopathy driven by the extracellular accumulation of misfolded amyloidogenic proteins, primarily immunoglobulin light chains and transthyretin (ATTR), with significant implications for the cardiac conduction system. This review highlights the intricate arrhythmogenic landscape of CA, encompassing structural remodeling, electromechanical uncoupling, and direct cytotoxicity, which collectively predispose patients to a range of rhythm disturbances, including AF, ventricular tachyarrhythmias, and conduction blockades. The distinct electrophysiological manifestations across amyloidosis subtypes underscore the critical need for early and precise diagnostic stratification through advanced imaging modalities, biomarker profiling, and rhythm monitoring technologies. Current therapeutic strategies, encompassing pharmacologic modulation, device implantation, and ablative interventions, must be precisely tailored to the underlying amyloid subtype and the specific arrhythmic phenotype to optimize hemodynamic stability and prognostic outcomes. Critically, the growing appreciation of CA as an etiologic substrate for arrhythmias and SCD mandates a paradigm shift toward integrative risk stratification frameworks and genotype-phenotype correlations. Future research must prioritize refining mechanistic understanding and therapeutic personalization, particularly through multi-omics profiling and artificial intelligence-driven predictive modeling.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.

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