Closing the diagnostic gap in transthyretin cardiac amyloidosis: red flags, modern imaging, and emerging therapies

Transthyretin cardiac amyloidosis (ATTR-CM) is an increasingly recognized, treatable, and still underdiagnosed cause of heart failure with preserved ejection fraction (HFpEF) and unexplained left ventricular hypertrophy in older adults, with a typical diagnostic delay of several years. We conducted a narrative review with a systematic literature search of PubMed and Embase (January 2000 to June 2026) using database-specific controlled vocabulary and free-text terms related to ATTR cardiomyopathy, clinical red flags, bone scintigraphy, monoclonal protein testing, cardiac magnetic resonance, tafamidis, acoramidis, vutrisiran, and emerging TTR-directed therapies. Two authors screened titles and abstracts, resolved disagreements by consensus, and prioritized multicenter cohorts, clinical trials, meta-analyses, systematic reviews, and guideline or consensus documents. Sixty-two references were included. Three practice points emerge from the literature. First, suspicion should be triggered by red flags such as bilateral carpal tunnel syndrome, lumbar spinal stenosis, spontaneous distal biceps tendon rupture, and the combination of increased ventricular wall thickness with low or normal QRS voltage. Second, the contemporary diagnostic pathway requires parallel bone scintigraphy and complete monoclonal protein screening; grade 2-3 myocardial uptake supports non-biopsy diagnosis of ATTR-CM only when monoclonal screening is negative and myocardial uptake is confirmed, preferably by SPECT or SPECT/CT. Third, treatment options now extend beyond tafamidis to acoramidis and vutrisiran, with amyloid-depleting antibodies under active investigation. We propose a pragmatic, resource-stratified diagnostic framework for targeted case-finding rather than population-level screening.