Predicting the Final Diagnosis in Patients With Suspected Amyloid Cardiomyopathy Referred for Tissue Biopsy

Background In patients with suspected amyloid cardiomyopathy (CM) and a monoclonal protein, tissue biopsy is mandatory to exclude amyloid light–chain CM (AL–CM), the subtype requiring urgent therapy. We aimed to develop a pragmatic approach to estimate the most likely final diagnosis before biopsy. Methods We studied a multicenter cohort of adults referred for biopsy because of suspected amyloid CM. Clinical, laboratory, ECG/echocardiographic and bone–tracer scintigraphy data were collected at initial suspicion. In patients with a monoclonal protein, we derived age cut–offs overall and by carpal tunnel syndrome (CTS), defined an age–based “grey zone” (74–83 years), and evaluated risk modifiers for AL–CM and transthyretin CM (ATTR–CM). We built a points–based algorithm for “grey–zone” patients. Clinical utility was assessed using decision–curve analysis. Results Among 602 patients (median age 76 years; 81% male), 524 (87%) had a monoclonal protein. In the monoclonal–protein subgroup, ATTR–CM accounted for 49%, AL–CM for 30%, and neither ATTR– nor AL–CM for 21%. Age ≤73 years was the Youden–optimal threshold favoring AL–CM (sensitivity 66%, specificity 78%), whereas age ›84 years made AL–CM unlikely (sensitivity 98%, negative predictive value 94%), defining a “grey zone” (n=261; ATTR–CM 63%, AL–CM 18%, no amyloid CM 20%). Within the gray zone, abnormal free light–chain ratio, positive urine immunofixation, proteinuria, and higher troponin T and N–terminal pro–B–type natriuretic peptide (NT–proBNP) favored AL–CM, while higher Perugini grade, male sex, greater interventricular septal thickness, and higher NT–proBNP favored ATTR–CM. Penalized models achieved cross–validated area under the curves of 0.87 (AL–CM) and 0.94 (ATTR–CM). A two–score algorithm identified small grey–zone subsets enriched for AL–CM (positive predictive value 81.5%, specificity 98%) or ATTR–CM (positive predictive value 95.2%, specificity 94%). DCA showed higher net benefit for score– and model–based strategies versus treat–all/treat–none across clinically relevant threshold probabilities, with consistent patterns across regions (Figure 1-2). Conclusions In patients with suspected amyloid CM and a monoclonal protein, age– and CTS–anchored stratification refined by a compact set of routine laboratory and imaging features provides actionable pre–biopsy probabilities and may help prioritize urgent biopsy and AL–directed work–up while definitive tissue typing is pursued.