Bridging the Gap in AL and ATTR Cardiac Amyloidosis: Integrating Histopathology, Biomarkers, and Multimodal Imaging for Subtype-Specific Diagnosis

Cardiac amyloidosis (CA) represents an increasingly recognized but historically underdiagnosed cause of restrictive cardiomyopathy and heart failure. CA is now understood to be more prevalent, particularly in older adults, as advancements in imaging and biomarker technologies have improved detection. The disease results from the misfolding of precursor proteins, primarily immunoglobulin light chains (in light chain (AL) amyloidosis) or transthyretin (in transthyretin (ATTR) amyloidosis), into insoluble fibrils that deposit in myocardial tissue. These deposits cause structural and functional cardiac impairment through both physical infiltration and cytotoxic mechanisms, leading to diastolic dysfunction, arrhythmias, and progressive heart failure. Understanding the molecular basis of amyloid formation and deposition has revealed subtype-specific mechanisms of toxicity and tissue tropism, highlighting the central role of protein instability, proteolytic cleavage, and oxidative stress in disease progression. Furthermore, increasing awareness of phenotypic variability and sex- or ethnicity-based diagnostic disparities has called for earlier recognition and differentiation of CA subtypes. Diagnostic precision is enhanced by a multimodal approach incorporating histopathology, biomarker staging, and advanced imaging techniques such as echocardiography, cardiac magnetic resonance, and nuclear scintigraphy. This review addresses our contemporary understanding of the molecular mechanisms, pathophysiologic cascade, and diagnostic evolution of AL and ATTR CA, emphasizing clinical progress. By delineating the biological mechanisms and tools for early identification, this paper aims to strengthen the framework for diagnosing and managing a disease that was once overlooked but is now at the forefront of modern cardiovascular medicine.