{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T11:46:44Z","timestamp":1782301604387,"version":"3.54.5"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Cardiac amyloidosis (CA) is a progressive infiltrative cardiomyopathy most commonly caused by transthyretin (ATTR) or immunoglobulin light chain (AL) amyloid deposition in the myocardium, microvasculature, and conduction system, although rarer forms, including apolipoprotein A-I amyloidosis (AApoA-I) and serum amyloid A amyloidosis (AA), may also involve the heart. Although traditionally viewed as a disorder driven mainly by extracellular fibril accumulation, growing evidence indicates that myocardial injury in CA also reflects the effects of soluble toxic intermediates, proteostasis failure, immune-inflammatory activation, and secondary structural remodeling. In this review, we compare the major biomolecular mechanisms underlying cardiac injury in ATTR and AL, beginning with precursor destabilization, misfolding, and oligomer formation, and extending to direct cardiomyocyte toxicity, mitochondrial and metabolic stress, calcium dyshomeostasis, fibroinflammatory remodeling, extracellular matrix reorganization, microvascular dysfunction, and autonomic and electrophysiological abnormalities. We further emphasize that ATTR and AL, while sharing several downstream pathological consequences, differ in their dominant upstream drivers and in the relative contribution of deposition-dependent versus soluble toxicity-mediated injury. This integrated mechanistic framework helps explain disease heterogeneity, persistent dysfunction despite amyloid reduction, and the need for subtype-specific therapeutic strategies. A more precise understanding of these interconnected pathways may improve early diagnosis, risk stratification, and the development of therapies targeting both the initiating protein abnormality and the downstream mechanisms responsible for ongoing myocardial dysfunction.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1832739","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T04:48:03Z","timestamp":1780030083000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Biomolecular mechanisms of cardiac amyloidosis and its cardiovascular pathological basis"],"prefix":"10.3389","volume":"17","author":[{"given":"Linlin","family":"Zhang","sequence":"first","affiliation":[{"name":"First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"YaTing","family":"Jiao","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, First Hospital of Shanxi Medical University","place":["Taiyuan, Shanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e7","DOI":"10.1161\/CIR.0000000000000792","article-title":"Cardiac amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart 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