Purpose: There is a need for early quantitative markers of potential treatment response in patients with hereditary transthyretin (ATTRv) amyloidosis to guide therapy. This study aims to evaluate changes in cardiac tracer uptake on bone scintigraphy in ATTRv amyloidosis patients on different treatments. Methods: In this retrospective cohort study, outcomes of 20 patients treated with the transthyretin (TTR) gene silencer patisiran were compared to 12 patients treated with a TTR-stabilizer. Changes in NYHA class, cardiac biomarkers in serum, wall thickness, and diastolic parameters on echocardiography and NYHA class during treatment were evaluated. Results: Median heart/whole-body (H/WB) ratio on bone scintigraphy decreased from 4.84 [4.00 to 5.31] to 4.16 [3.66 to 4.81] (p < .001) in patients treated with patisiran for 29 [15–34] months. No changes in the other follow-up parameters were observed. In patients treated with a TTR-stabilizer for 24 [20 to 30] months, H/WB ratio increased from 4.46 [3.24 to 5.13] to 4.96 [ 3.39 to 5.80] (p = .010), and troponin T increased from 19.5 [9.3 to 34.0] ng/L to 20.0 [11.8 to 47.8] ng/L (p = .025). All other parameters did not change during treatment with a TTR-stabilizer. Conclusion: A change in cardiac tracer uptake on bone scintigraphy may be an early marker of treatment-specific response or disease progression in ATTRv amyloidosis patients.

Purpose: Transthyretin (ATTR) amyloidosis is a progressive protein misfolding disease with frequent cardiac involvement. This review aims to determine the value of PET in diagnosis, assessment of disease progression or treatment response and its relation to clinical outcome in follow-up of ATTR amyloid cardiomyopathy (ATTR-CM) patients. Methods: Medline, Cochrane Library, Embase and Web of Science databases were searched, from the earliest date available until December 2022, for studies investigating the use of PET in ATTR-CM patients. Studies containing original data were included, except for case reports. Risk of bias was assessed by QUADAS-2. Results: Twenty-one studies were included in this systematic review, investigating five different tracers: carbon-11 Pittsburgh compound B ([¹¹C]PIB), fluorine-18 Florbetaben ([¹⁸F]FBB), fluorine-18 Florbetapir ([¹⁸F]FBP), fluorine-18 Flutemetamol ([¹⁸F]FMM) and fluorine-18 Sodium Fluoride (Na[¹⁸F]F). In total 211 ATTR amyloidosis patients were included. A majority of studies concluded that [¹¹C]PIB, [¹⁸F]FBP and Na[¹⁸F]F can distinguish ATTR amyloidosis patients from controls, and that [¹¹C]PIB and Na[¹⁸F]F, but not [¹⁸F]FBP, can distinguish ATTR-CM patients from patients with cardiac light chain amyloidosis. Evidence on the performance of [¹⁸F]FBB and [¹⁸F]FMM was contradictory. No studies on the use of PET in follow-up were found. Conclusion: [¹¹C]PIB, Na[¹⁸F]F and [¹⁸F]FBP can be used to diagnose cardiac amyloidosis, although [¹⁸F]FBP may not be suitable for the distinction of different types of amyloid cardiomyopathy. No studies on PET in the follow-up of ATTR amyloidosis patients were found. Future research should focus on the use of these PET tracers in the follow-up of ATTR amyloidosis patients.

Cardiovascular diseases (CVD) are the leading cause of death worldwide and have an increasing impact on society. Precision medicine, in which optimal care is identified for an individual or a group of individuals rather than for the average population, might provide significant health benefits for this patient group and decrease CVD morbidity and mortality. Molecular imaging provides the opportunity to assess biological processes in individuals in addition to anatomical context provided by other imaging modalities and could prove to be essential in the implementation of precision medicine in CVD. New developments in single-photon emission computed tomography (SPECT) and positron emission tomography (PET) systems, combined with rapid innovations in promising and specific radiopharmaceuticals, provide an impressive improvement of diagnostic accuracy and therapy evaluation. This may result in improved health outcomes in CVD patients, thereby reducing societal impact. Furthermore, recent technical advances have led to new possibilities for accurate image quantification, dynamic imaging, and quantification of radiotracer kinetics. This potentially allows for better evaluation of disease activity over time and treatment response monitoring. However, the clinical implementation of these new methods has been slow. This review describes the recent advances in molecular imaging and the clinical value of quantitative PET and SPECT in various fields in cardiovascular molecular imaging, such as atherosclerosis, myocardial perfusion and ischemia, infiltrative cardiomyopathies, systemic vascular diseases, and infectious cardiovascular diseases. Moreover, the challenges that need to be overcome to achieve clinical translation are addressed, and future directions are provided.

Purpose: Bone scintigraphy is key to non-invasively diagnosing wild-type transthyretin (ATTRwt) amyloidosis, and is mainly used to assess cardiac radiotracer uptake. However, extracardiac radiotracer uptake is also observed. We investigated whether intensity of soft tissue radiotracer uptake is associated with amyloid load in subcutaneous abdominal fat tissue and with mortality. Methods: This prospective cohort study included 94 ATTRwt amyloidosis patients and 26 amyloid-negative heart failure controls who underwent whole-body [^99mTc]Tc-hydroxydiphosphonate scintigraphy. Site-to-background ratios were calculated for heart, elbows, subcutaneous tissue, shoulders and wrists on anterior planar bone scintigraphy images using rib and whole-body radiotracer uptake as background. Fat tissue aspirates were stained with Congo red to grade amyloid load. Site-to-rib ratios were compared between ATTRwt amyloidosis patients and controls, and associations of site-to-background ratio with Congo red score and all-cause mortality were studied. Results: ATTRwt amyloidosis patients had higher soft tissue-to-rib, heart-to-rib and heart-to-whole body ratios compared with controls. The intensity of soft tissue uptake was positively associated with amyloid load in fat tissue in ATTRwt amyloidosis patients. Estimated glomerular filtration rate, N-terminal brain natriuretic propeptide, high-sensitivity cardiac troponin T (hs-cTnT), and the prognostic Mayo and NAC staging system were associated with all-cause mortality in univariable models. Soft tissue/rib ratio, hs-cTnT and the prognostic staging systems were the only two variables that were independently associated withall-cause mortality. Conclusion: Soft tissue radiotracer uptake on bone scintigraphy in ATTRwt amyloidosis patients is positively associated with amyloid load in abdominal fat tissue and is independently associated with mortality.

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) is an under-recognized aetiology of heart failure (HF), necessitating early detection for timely treatment. Our study aimed to differentiate patients with ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF patients by identifying and validating circulating protein biomarkers. In addition, we measured the same biomarkers in patients with cardiomyopathy due to light chain amyloidosis (AL)-CM to gain disease-specific insights. In this observational study, serum concentrations of 363 protein biomarkers were measured in a discovery cohort consisting of 73 ATTRwt-CM, 55 AL-CM, and 59 ATTRwt-negative HFpEF/HFmrEF patients, using multiplex proximity extension assays. Sparse partial least squares analyses showed overlapping ATTRwt-CM and AL-CM biomarker profiles with clear visual differentiation from ATTRwt-negative patients. Pathway analyses with g:Profiler revealed significantly up-regulated proteoglycans (PG) and cell adhesion pathways in both ATTRwt-CM and AL-CM. Penalized regression analysis revealed that the proteoglycan decorin (DCN), lysosomal hydrolase alpha-L-iduronidase (IDUA) and glycosyl hydrolase galactosidase β-1 (GLB-1) most effectively distinguished ATTRwt-CM from ATTRwt-negative patients (R² = 0.71). In a prospective validation cohort of 35 ATTRwt-CM patients and 25 ATTRwt-negative patients, DCN and IDUA significantly predicted ATTRwt-CM in the initial analysis (DCN: OR 3.3, IDUA: OR 0.4). While DCN remained significant after correcting for echocardiographic parameters, IDUA did not. DCN showed moderate discriminative ability (AUC, 0.74; 95% CI, 0.61–0.87; sensitivity, 0.91; specificity, 0.52) as did IDUA (AUC, 0.78; 95% CI, 0.65–0.91; sensitivity, 0.91; specificity, 0.61). A model combining clinical factors (AUC 0.92) outperformed DCN but not IDUA, a combination of the biomarkers was not significantly better. Neither DCN nor IDUA correlated with established disease markers. ATTRwt-CM has a distinctly different biomarker profile compared with HFpEF/HFmrEF, while ATTRwt-CM patients share a similar biomarker profile with AL-CM patients characterized by up-regulation of proteoglycans and cell-adhesion pathways. The biomarkers DCN and IDUA show the potential to serve as an initial screening tool for ATTTRwt-CM. Further research is needed to determine the clinical usefulness of these and other extracellular matrix components in identifying ATTRwt-CM.

Cardiac sympathetic neuronal dysfunction is an early marker in wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt-CM). [¹²³I]-MIBG imaging evaluates cardiac sympathetic innervation but lacks volumetric activity quantification in current methods. This study aims to quantify cardiac sympathetic neuronal dysfunction in ATTRwt-CM using [¹²³I]-MIBG SPECT/CT and correlate findings with functional and structural cardiac parameters from echocardiogram and cardiac magnetic resonance imaging (CMR). We conducted a single-center, descriptive, cross-sectional study to quantify absolute myocardial sympathetic function in ATTRwt-CM using [¹²³I]-MIBG SPECT/CT. Retrospective reconstruction allowed for absolute tracer-uptake quantification of the left ventricle, overall and segmented, in kBq/mL, SUV and percentage of the injected dose (%ID). Echocardiography, CMR, and bone scintigraphy were performed according to clinical standards. Segmented [¹²³I]-MIBG SPECT/CT values were correlated with global longitudinal strain (GLSS) on echocardiography, native-T1, and extracellular volume (ECV) on CMR using SPECT/CT fused with CMR. Twenty-nine ATTRwt-CM patients (75.8±6.6 years, 90% male) were prospectively included. All exhibited cardiac sympathetic neuronal dysfunction, with a median late heart-to-mediastinum ratio of 1.69[1.45-1.89] and a washout rate of 22.7% (16.4-27.3%). SUV_mean, SUV_peak, SUV_max and %ID were 1.80 ± 0.78, 3.84 ± 1.41, 4.46 ± 1.68 and 0.46 ± 0.18 respectively, correlating with semi-quantitative [¹²³I]-MIBG measures. No correlations were found with GLSS on echocardiography or native T1 and ECV on CMR. The current study demonstrates the feasibility of volumetric quantification of [¹²³I]-MIBG SPECT/CT in ATTRwt-CM. SUV_mean, SUV_peak, SUV_max and %ID correlate with semi-quantitative measures but not with key cardiac parameters on echocardiography or CMR. This confirms the sensitivity of [¹²³I]-MIBG SPECT/CT to different aspects of cardiac function or pathology. EudraCT ref. 2020-003350-72, retrospectively registered 20 March 2023. https://classic. gov/ct2/show/NCT05776212.