Cardiac sympathetic innervation with [123I]-MIBG SPECT/CT for early prediction of treatment response in wild-type transthyretin amyloidosis: The I-NERVE study

Introduction Transthyretin amyloidosis (ATTR) predominantly affects the heart, leading to progressive cardiomyopathy (CM) with poor prognosis. Early detection is important, as therapies such as stabilizer tafamidis are most beneficial when initiated early. However, reliable markers to predict treatment response are lacking. [¹²³I]-MIBG scintigraphy allows quantification of autonomic cardiac dysfunction and has shown prognostic value in hereditary ATTR. This prospective study aimed to quantify cardiac sympathetic innervation with [¹²³I]-MIBG scintigraphy in ATTR-CM patients for early prediction of responders and non-responders. Methods Patients with confirmed ATTR-CM underwent [¹²³I]-MIBG scintigraphy at baseline and after one year of tafamidis therapy. Cardiac sympathetic innervation was quantified by calculating early (15 min) and late (4 hr) heart-to-mediastinum ratio (HMR), and washout rate (WR (%)). Additional evaluations included laboratory assessments, 6-minute walk test (6MWT), Holter monitoring, transthoracic echocardiography, cardiovascular magnetic resonance, and Kansas City Cardiomyopathy Questionnaire (KCCQ). Non-responders were defined as patients showing disease progression according to the criteria proposed by Garciá-Pavía et al. Correlations between changes in [123I]-MIBG parameters and clinical outcomes, as well as [123I]-MIBG differences of responders and non-responders, were evaluated using Spearman correlation and Mann-Whitney U tests. Results Thirty-five patients were included, with a mean age of 76±6 years (90% males). Mean late HMR was 1.72±0.42 at baseline and 1.73±0.44 at follow-up. The WR at baseline was 22.6±10.5% and 21.0±9.8% at follow-up. No significant correlations were observed between changes in late HMR or WR, and changes in laboratory values, echocardiography, 6MWT, or KCCQ scores. Similarly, clinical and functional parameters did not differ between patients with increased versus decreased late HMR or WR. Baseline late HMR was lower in non-responders than responders to tafamidis (median late HMR baseline: 1.5 vs 1.8; p = 0.048) and was also significantly lower at follow-up (median late HMR follow-up: 1.52 vs 1.87; p = 0.039). WR was significantly higher at follow-up for non-responders (median 25.5 vs 17; p = 0.024). Conclusion This prospective study showed that decreased late HMR, reflecting more severe cardiac sympathetic denervation, was associated with poor treatment response. WR at follow-up was significantly higher in non-responders, indicating worsened cardiac denervation. Overall, non-responders to treatment demonstrated advanced autonomic dysfunction, supporting the potential utility of late HMR on [¹²³I]-MIBG scintigraphy as a predictive marker for treatment response. These findings highlight the potential of [¹²³I]-MIBG imaging for early detection of cardiac sympathetic dysfunction in ATTR-CM patients.Figure 1Table 1