Monitoring the Electrical Phenotype of Transthyretin Amyloid Cardiomyopathy in the Era of Disease-Modifying Therapy

The clinical landscape of transthyretin amyloid cardiomyopathy (ATTR-CM) has changed substantially over the past decade. Advances in diagnostic imaging, increased disease awareness, and the introduction of disease-modifying therapies (DMTs) have transformed ATTR-CM from a relentlessly progressive infiltrative cardiomyopathy into a chronic cardiovascular disease requiring long-term management. Tafamidis was the first major therapeutic breakthrough, and additional transthyretin stabilizers and RNA-silencing therapies have further expanded treatment options.^1–3 Real-world studies have also supported the clinical effectiveness of tafamidis in routine practice.⁴ As survival improves, clinical attention is increasingly shifting from diagnosis and treatment initiation to longitudinal disease monitoring and management.

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In this context, the electrical manifestations of ATTR-CM have emerged as a clinically relevant yet incompletely understood aspect of disease progression. Amyloid infiltration affects not only the working myocardium, but also the specialized conduction system, resulting in a broad spectrum of electrical abnormalities, including atrial arrhythmias, sinus node dysfunction, atrioventricular conduction delay, bundle branch block, and ventricular dyssynchrony. Collectively, these abnormalities may be viewed as components of an ATTR-CM “electrical phenotype”, a multidimensional manifestation of cardiac amyloid involvement that extends beyond conventional measures of heart failure severity.

Despite their clinical importance, electrical abnormalities often receive less systematic attention than biomarkers, ventricular function or heart failure symptoms. Consequently, conduction disturbances are frequently recognized only after symptomatic bradycardia, syncope, advanced atrioventricular block or worsening heart failure has developed. Although increasing attention has been directed toward atrial arrhythmias in recent years, the longitudinal assessment of conduction system disease remains relatively underexplored.⁵

In this issue of the Journal, Hamamoto et al. provide important insights into this knowledge gap by evaluating the progression of conduction abnormalities in patients with wild-type ATTR-CM receiving tafamidis therapy.⁶ They demonstrate significant prolongation of both the PQ interval and QRS duration during 1 year of follow-up, despite ongoing treatment. Furthermore, native myocardial T1 and high-sensitivity cardiac troponin T (hs-cTnT) were associated with intraventricular conduction disturbance, whereas native T1 was associated with baseline atrioventricular and intraventricular conduction abnormalities.

These findings highlight a fundamental reality of contemporary ATTR-CM care: electrical remodeling may continue despite DMT. Current therapies effectively target transthyretin destabilization and amyloid formation, but their ability to prevent progression of established conduction system involvement remains uncertain. Clinical stability, therefore, does not necessarily imply electrical stability.

Importantly, these observations were made in patients receiving tafamidis therapy. In the pre-DMT era, progressive conduction disease may have been overshadowed by heart failure progression and limited survival. As patients live longer under DMT, the natural history of electrical remodeling may become increasingly apparent. Recent long-term data from tafamidis-treated patients further support the need for surveillance beyond traditional heart failure endpoints.⁷

The association of native T1 and hs-cTnT with conduction disease progression is particularly noteworthy. Native T1 mapping has emerged as a robust marker of myocardial amyloid burden and tissue injury, whereas hs-cTnT reflects ongoing myocardial damage. Their association with QRS prolongation suggests that electrical remodeling progresses in parallel with structural myocardial involvement. These markers may therefore help identify patients at increased risk before clinically significant conduction disease becomes apparent.

The electrical phenotype of ATTR-CM should not be regarded as a single entity. Emerging evidence suggests that predictors of atrial arrhythmias differ from those associated with conduction disease progression. Kuyama et al. demonstrated that right atrial peak longitudinal strain and hs-cTnT were associated with new-onset atrial fibrillation (AF) in ATTR-CM, whereas native T1 and QRS duration showed limited predictive value.⁸ Similarly, Otsuka et al. reported that atrial lesions and diastolic dysfunction were associated with AF in patients with cardiac amyloidosis.⁹ In contrast, Hamamoto et al. identified native T1 and hs-cTnT as markers associated with conduction system involvement and progression.⁶

Taken together, these observations suggest that different components of the electrical phenotype reflect distinct pathophysiological processes and therefore require different surveillance strategies. Atrial arrhythmias primarily reflect atrial remodeling and dysfunction, whereas conduction disturbances may indicate progressive amyloid infiltration of the His–Purkinje system and ventricular conduction network. Ventricular dyssynchrony may represent another downstream manifestation of electrical remodeling. Accordingly, a uniform approach to electrical surveillance is unlikely to be sufficient. Risk assessment for atrial arrhythmias may rely more heavily on atrial functional evaluation, whereas surveillance for conduction disease progression may benefit from integrating ECG findings with biomarkers and advanced imaging parameters.

As patients survive longer under DMT, electrical complications are likely to become increasingly prominent determinants of morbidity, functional capacity, and quality of life. Earlier recognition of electrical deterioration may facilitate closer follow-up and more informed clinical decision-making regarding rhythm management, pacemaker implantation, and other device therapies when clinically indicated. Emerging experience with cardiac resynchronization therapy further suggests that ventricular dyssynchrony may have significant clinical implications during long-term follow-up, even in the era of DMT.¹⁰

The present study also highlights the continuing value of serial ECG. Although advanced imaging modalities and circulating biomarkers have transformed the evaluation of ATTR-CM, the ECG remains inexpensive, widely available, and uniquely suited to monitoring progressive electrical remodeling (Figure). Careful longitudinal assessment of the PQ interval, QRS duration, and rhythm abnormalities may provide clinically meaningful information that complements imaging and biomarker evaluation.

Figure.

Monitoring the electrical phenotype of transthyretin amyloid cardiomyopathy (ATTR-CM). As survival improves with disease-modifying therapies (DMTs), electrical manifestations of ATTR-CM are becoming increasingly relevant during long-term follow-up. Atrial arrhythmias, conduction disease, and ventricular dyssynchrony may reflect distinct pathophysiological processes and may therefore require different surveillance strategies. Integration of ECG findings, biomarkers, and advanced imaging parameters may facilitate earlier recognition of electrical disease progression and support comprehensive ATTR-CM management. AF, atrial fibrillation; AFL, atrial flutter; AT, atrial tachycardia; AVB, atrioventricular block; CLBBB, complete left bundle branch block; CRT, cardiac resynchronization therapy; hs-cTnT, high-sensitivity cardiac troponin T; RA, right atrial.

Several important questions remain unanswered. Whether different DMTs exert differential effects on conduction system progression is unknown. It also remains unclear whether serial assessment of native T1, hs-cTnT, atrial function or ECG parameters can improve individualized surveillance strategies. Prospective studies incorporating arrhythmic outcomes, device implantation, and longer-term follow-up are warranted.

As therapeutic advances improve survival, attention must increasingly shift toward complications that influence long-term functional status and quality of life. The next frontier in ATTR-CM may not simply be preventing amyloid deposition, but rather understanding how the disease continues to evolve electrically despite successful DMT. Systematic assessment of the electrical phenotype, including atrial arrhythmias, conduction disturbances, and ventricular dyssynchrony, may become an essential component of comprehensive ATTR-CM management in the years ahead.

Disclosures

N.T. is a member of Circulation Reports’ Editorial Team.