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Imbalances in native protein-stabilizing and elementary breakdown cellular mechanisms are postulated as potential causes for affecting transthyretin structural integrity and myocardial fibril deposition. Noncoding variants, epigenetic and environmental factors, as well as gut microbiome derangements may serve as disease-modifying factors that feature detrimental amyloidogenic organ involvement and impact disease severity. Organ amyloid deposition varies widely among different carriers of a genetic transthyretin variant. The genotype-phenotype interdependence causes unpredictable phenotypic penetrance that results in a variety of signs and symptoms and patient outcomes. Cardiovascular biomarkers and multimodality imaging may identify initial amyloidogenic organ involvement. These early clinical clues through the course of hATTR-CA offer a window of opportunity for early treatment onset to cease disease progression and alter prognosis. Identifying at-risk patients requires information on the genetic background of probands and their relatives. Initiatives to reveal asymptomatic gene carriers early in the disease should be encouraged, as it necessitates stringent patient follow-up and immediate treatment onset to reduce the burden of heart failure hospitalization and mortality in hATTR-CA.<\/jats:p>","DOI":"10.1161\/circheartfailure.124.012469","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T09:01:08Z","timestamp":1741942868000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Hereditary Transthyretin Cardiac Amyloidosis With the p.V142I Variant: Mechanistic Insights and Diagnostic Challenges"],"prefix":"10.1161","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-1245-0396","authenticated-orcid":true,"given":"Simon","family":"Vanhentenrijk","sequence":"first","affiliation":[{"name":"Kaufman Center for Heart Failure Treatment and Recovery, Heart Vascular and Thoracic Institute, Cleveland Clinic, OH (S.V., W.H.W.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2400-3196","authenticated-orcid":true,"given":"Justin L.","family":"Grodin","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas (J.L.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7663-4902","authenticated-orcid":true,"suffix":"Jr","given":"Silvio Nunes","family":"Augusto","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, OH (S.N.A., W.H.W.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.H. 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