Cardiac Amyloidosis: A Narrative Review of Diagnostic Advances and Emerging Therapies

1. Introduction

Amyloidosis is a disorder characterized by the extracellular accumulation of fibrils composed of low-molecular-weight subunits derived from various serum proteins. This condition can affect multiple organs, with cardiac, renal, hepatic, and autonomic nervous system involvements being the primary contributors to morbidity and mortality. Several factors increase the risk of developing amyloidosis, including advanced age, male sex, African ancestry, chronic or infectious diseases, and a family history of the condition, as certain types of amyloidosis are hereditary [1external link, opens in a new tab]. Moreover, the transthyretin (TTR) Ile122 variant—strongly associated with cardiac amyloidosis (CA) in individuals of African descent—has an allele frequency of 66/3376 (2.0%) among African-Americans across the U.S., suggesting it is a common, often unrecognized contributor to cardiac disease in this population [2external link, opens in a new tab].

CA is characterized by the extracellular buildup of misfolded proteins within the heart, marked by a unique histological feature: green birefringence under cross-polarized light following Congo red staining. CA involves the extracellular accumulation of fibrillar and insoluble protein aggregates within the myocardium, leading to cardiac dysfunction [3external link, opens in a new tab]. Although over 30 types of amyloidogenic proteins have been identified [4external link, opens in a new tab], five of them affect the heart, including immunoglobulin heavy and light chain (AL), transthyretin (TTR), amyloid A, and apolipoprotein A1. Among these, the AL and ATTR types (wild-type [ATTRwt] and hereditary/variant [ATTRv]) account for 95% of all CA cases [5external link, opens in a new tab]. The pathogenesis of CA starts with the misfolding of precursor proteins, which form insoluble fibrils that deposit throughout the myocardial interstitium and perivascular spaces, ultimately disrupting the normal tissue architecture and compliance [6external link, opens in a new tab,7external link, opens in a new tab]. As these deposits accumulate, the heart develops a restrictive physiology characterized by impaired ventricular filling and, over time, systolic dysfunction [8external link, opens in a new tab]. Despite its clinical significance, CA is often underdiagnosed: the systematic screening of older adults with heart failure and preserved ejection fraction (HFpEF) has revealed CA in up to 16% of these patients, underscoring a significant diagnostic gap in this population [9external link, opens in a new tab].

The infiltrative process in the heart results in progressive myocardial dysfunction, often accompanied by the impairment of the cardiac conduction system. Amyloid cardiomyopathy is increasingly recognized as a significant yet frequently underdiagnosed cause of heart failure and cardiac arrhythmias, particularly in older adults. In parallel with mechanical impairment, amyloid fibrils infiltrate the cardiac conduction system—including the sinoatrial and atrioventricular nodes and the His–Purkinje network—creating areas of conduction block and promoting reentrant circuits [9external link, opens in a new tab]. As a result, atrial fibrillation (AF) arises in up to 73% of patients with transthyretin amyloidosis, especially those of an advanced age, a higher disease stage, and enlarged left atrial volumes [10external link, opens in a new tab]. The combination of a poor rate control tolerance and a markedly elevated stroke risk makes AF management challenging; current evidence supports early rhythm-control strategies and indicates that novel oral anticoagulants provide a thromboembolic protection comparable to warfarin with fewer major bleedings, while timely AF ablation may reduce both mortality and heart-failure hospitalizations [10external link, opens in a new tab,11external link, opens in a new tab]. Conduction blocks and ventricular tachyarrhythmias also occur frequently, often necessitating permanent pacing for symptomatic bradyarrhythmias or advanced atrioventricular blocks [12external link, opens in a new tab]. Although implantable cardioverter-defibrillators (ICDs) are used for sudden cardiac death (SCD) prevention, their impact on the overall survival in CA remains uncertain, as a high mortality persists despite device therapy [13external link, opens in a new tab].

Although traditionally regarded as a rare condition, emerging evidence indicates that cardiac amyloidosis is often overlooked as a contributing factor to common cardiac diseases and syndromes. Recent advancements in cardiac imaging, diagnostic techniques, and therapeutic approaches have significantly enhanced the identification and management of this condition [14external link, opens in a new tab].

Advancements in cardiac imaging and increased physician awareness have significantly improved the diagnosis of cardiac amyloidosis over the past decade. Cardiac involvement in amyloidosis is associated with a poor prognosis, making early detection essential. A timely diagnosis is critical for implementing appropriate treatment strategies that can potentially alter the disease’s natural course and improve patient outcomes [15external link, opens in a new tab]. This review highlights that non-invasive imaging modalities and serum biomarker analyses are key to reducing diagnostic delays. New therapeutic developments, including gene-editing technologies and RNA-based therapies, show promise in early trials. Multidisciplinary management and increased awareness are crucial for timely diagnosis and treatment optimization.