OBJECTIVE: To evaluate the incremental prognostic value of a blunted heart rate response (HRR) to regadenoson beyond PET-derived myocardial flow parameters. BACKGROUND: A blunted HRR during pharmacologic stress with rega...OBJECTIVE: To evaluate the incremental prognostic value of a blunted heart rate response (HRR) to regadenoson beyond PET-derived myocardial flow parameters. BACKGROUND: A blunted HRR during pharmacologic stress with regadenoson, an adenosine A2A receptor agonist, may reflect autonomic dysfunction and heightened cardiovascular (CV) risk. Whether HRR provides prognostic information beyond stress myocardial blood flow (sMBF) and myocardial flow reserve (MFR) remains uncertain. METHODS: We retrospectively analyzed consecutive rest-stress Rb PET/CT studies performed between 2016 and 2022. Abnormal sMBF and MFR were defined as less than 1.8 mL/min/g and <2.0, respectively. HRR was calculated as (peak HR - rest HR)/rest HR and considered blunted if less than 20%. We compared differences in major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, or heart failure hospitalization) between patients with blunted and normal HRR using multivariable Cox regression, stratified by sMBF and MFR. Nonlinear associations between HRR and MACE were evaluated using restricted cubic splines. Incremental prognostic value was assessed by changes in the area under the receiver-operating characteristic curve (AUC) and net reclassification index (NRI). RESULTS: Among 4611 patients (63 ± 11 years; 54% female), 1263 (27%) had blunted HRR. These patients had a higher prevalence of abnormal sMBF (49% vs 27%) and MFR (66% vs 30%). Over a median follow-up of 3.3 years (IQR 1.8-5.1), MACE rates were higher among patients with blunted HRR (16.2 vs 5.5 events/100 patient-years; adjusted HR 1.70 [95% CI: 1.50-1.94]; P < .001), irrespective of sMBF or MFR status. Risk increased progressively with lower HRR. Adding HRR to a model with key clinical characteristics and MBF improved prognostic discrimination and reclassification (ΔAUC +0.017; NRI 0.12; all P < .001). CONCLUSIONS: Blunted HRR to regadenoson is independently associated with higher CV risk and provides incremental prognostic value beyond PET myocardial flow.
Cardiac amyloidosis (CA) has rapidly transitioned from an underrecognized cause of heart failure to a treatable protein-misfolding cardiomyopathy, driven by advances in transthyretin (TTR) stabilization and gene silencin...Cardiac amyloidosis (CA) has rapidly transitioned from an underrecognized cause of heart failure to a treatable protein-misfolding cardiomyopathy, driven by advances in transthyretin (TTR) stabilization and gene silencing, and immunotherapy to control monoclonal light chain production. Noninvasive diagnosis of transthyretin cardiac amyloidosis (ATTR) using technetium-99m bone-avid scintigraphy is now routine, yet these tracers do not bind amyloid and offer limited amyloid specificity, quantification, or monitoring of response to therapy. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) agents that directly engage amyloid or key downstream processes (fibroblast activation, inflammation, denervation) may redefine the diagnostic algorithm, phenotyping, risk stratification, and longitudinal assessment. Among these, iodine [I]evuzamitide (AT-01), a radioiodinated, pan-amyloid-binding peptide targeting amyloid fibrils and amyloid associated heparan sulfate proteoglycans, has emerged as the first amyloid-specific PET radiotracer to receive U.S. FDA Breakthrough Therapy designation for CA and has completed a Phase 3 pivotal evaluation. [F]Florbetaben is similarly poised in a pivotal Phase 3 study. Herein, we summarize 1) Emerging radiotracers primed for clinical availability, including the pan-amyloid peptide tracers, [I]evuzamitide and [Tc]p5+14, the stilbene-based small molecule [F]florbetaben, and the protein-based radiotracer, [Tc]aprotinin; 2) Research-focused, Aβ amyloid radiotracers and their performance in CA ([C]PiB; [F]florbetapir, [F]flutemetamol; and newer [F]florbetazine); and 3) Adjunct radiotracers for exploring myocardial microenvironment ([Ga]FAPI, and others), emphasizing rationale for use, opportunities, synergies, strengths, limitations, and regulatory status. Finally, we outline future research and molecular targets to elucidate the pathology and the impact of novel amyloid therapeutics as they become available.
Echocardiography and cardiac magnetic resonance (CMR) can demonstrate features of myocardial infiltration in cardiac amyloidosis, but cannot independently establish a definitive diagnosis or determine amyloid subtype. Ac...Echocardiography and cardiac magnetic resonance (CMR) can demonstrate features of myocardial infiltration in cardiac amyloidosis, but cannot independently establish a definitive diagnosis or determine amyloid subtype. Accurate diagnosis requires integration of imaging with clinical assessment, laboratory testing for monoclonal gammopathy, radionuclide scintigraphy, and tissue biopsy when indicated. Echocardiography remains the first-line modality, identifying characteristic structural and functional abnormalities and offering prognostic information, with emerging innovations such as artificial intelligence showing promise for earlier detection. CMR adds high-resolution tissue characterization through late gadolinium enhancement, T1 mapping, and extracellular volume quantification, enabling early detection, disease staging, and longitudinal monitoring. computed tomography (CT)-derived extracellular volume provides a practical alternative when CMR is unavailable and may be incorporated opportunistically during routine cardiac CT studies. Integrating these modalities within contemporary diagnostic pathways allows tailored sequencing based on clinical context, improving diagnostic accuracy and guiding decisions regarding radionuclide imaging and biopsy. A multimodality, pathway-based approach ensures timely diagnosis, appropriate subtype differentiation, and optimal management across the spectrum of suspected and established cardiac amyloidosis.
Cardiac amyloidosis (CA) is characterized by cardiac amyloid fibril deposition leading to organ dysfunction. The two most common forms are transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) and immunoglobulin light cha...Cardiac amyloidosis (CA) is characterized by cardiac amyloid fibril deposition leading to organ dysfunction. The two most common forms are transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) and immunoglobulin light chain cardiomyopathy (AL-CM). Treatment of CA includes disease-modifying therapies and treating symptoms and cardiac co-morbidities. Patients with heart failure and CA are managed with diuretics for volume optimization, but other guideline-directed medical therapies should be used on a case-by-case basis. Current disease-modifying therapies for ATTR-CM include TTR tetramer stabilizers and gene silencers. Investigational therapies include Clustered Regularly Interspaced Short Palindromic Repeats and associated Cas9 endonuclease (CRISPR-Cas9) systems and amyloid depleters. Current disease-modifying therapies for AL-CM include anti-plasma cell dyscrasia therapies. Investigational therapies include stabilizers and depleters. Nuclear scintigraphy is used to differentiate CA sub-type with no established role for nuclear imaging in therapeutic monitoring to date. However, given nuclear imaging and radiotracer advances, further research is being conducted regarding a nuclear imaging-based approach to assess amyloid burden and organ response to therapy.
Transthyretin amyloid cardiomyopathy (ATTR-CM) has transitioned from a rare, untreatable condition to a prevalent and treatable cause of heart failure, driven by advances in disease-modifying therapies and the emergence...Transthyretin amyloid cardiomyopathy (ATTR-CM) has transitioned from a rare, untreatable condition to a prevalent and treatable cause of heart failure, driven by advances in disease-modifying therapies and the emergence of cardiac amyloid radionuclide imaging (CARI) as a reliable noninvasive diagnostic modality. Despite widespread adoption, substantial global heterogeneity persists in access, technical implementation, and diagnostic performance for CARI. This review synthesizes contemporary evidence on the global state of CARI, highlighting regional disparities in infrastructure, referral patterns, and adherence to best-practice standards. Furthermore, the review proposes a set of pragmatic strategies to enhance global CARI implementation, including standardized protocols prioritizing SPECT-based interpretation, targeted education, clearer guidance for screening high-risk populations, and development of international registries. Addressing these barriers is essential to ensure equitable, high-quality diagnosis and to fully realize the clinical impact of CARI in ATTR-CM.
Cardiac amyloid radionuclide imaging (CARI) with single-photon emission computed tomography (SPECT) bone-avid tracers plays a key role in the noninvasive detection of transthyretin cardiac amyloidosis (CA). In addition,...Cardiac amyloid radionuclide imaging (CARI) with single-photon emission computed tomography (SPECT) bone-avid tracers plays a key role in the noninvasive detection of transthyretin cardiac amyloidosis (CA). In addition, newer amyloid-binding tracers used with positron emission tomography (PET) can identify different types of CA. These SPECT and PET CARI techniques generate "hot-spot" images that represent tracer accumulation in regions of amyloid deposition and are typically interpreted visually by comparing myocardial uptake with reference regions such as bone or the blood pool. Although qualitative interpretation of SPECT CARI has been effective for diagnosis, it has notable limitations. This review focuses on methods for quantitative SPECT and PET CARI, emphasizing the need for standardization and its potential role in early detection of cardiac amyloidosis, evaluation of disease burden, risk prediction, and longitudinal monitoring of disease progression.
Cardiac amyloidosis (CA) has transitioned from a rare, frequently fatal disease to an increasingly recognized cause of heart failure, driven by heightened awareness, noninvasive diagnostic strategies, and the advent of d...Cardiac amyloidosis (CA) has transitioned from a rare, frequently fatal disease to an increasingly recognized cause of heart failure, driven by heightened awareness, noninvasive diagnostic strategies, and the advent of disease-modifying therapies. As a result, molecular imaging has become central to contemporary management by providing signals that reflect underlying disease biology. Transthyretin CA predominantly involves progressive extracellular fibril accumulation causing myocardial stiffening, whereas light-chain CA is characterized by early myocardial dysfunction mediated by direct proteotoxic effects of circulating light chains in addition to extracellular fibril accumulation. These divergent mechanisms may underlie different behaviors of diagnostic imaging such as bone-avid scintigraphy and β-sheet-binding positron emission tomography tracers. In this compendium review, we integrate pathophysiological insights across major and rarer amyloid subtypes with nuclear imaging and contextualize these mechanisms through clinical phenotypes, red flags, and risk stratification tools.
Patel KK, Maddahi J, Agostini D
… +12 more, Bax JJ, Beanlands RSB, Berman D, Dorbala S, Heller GV, Knuuti JM, Pelletier-Galarneau M, Tamaki N, Thompson D, Somer EJ, Udelson JE, Bateman TM
J Nucl Cardiol
· 2026 May · PMID 42128226
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BACKGROUND: Noninvasive assessment of coronary artery disease (CAD) in obese patients is challenging due to suboptimal image quality. We performed a prespecified secondary analysis of obese patients from the second Phase...BACKGROUND: Noninvasive assessment of coronary artery disease (CAD) in obese patients is challenging due to suboptimal image quality. We performed a prespecified secondary analysis of obese patients from the second Phase III trial of flurpiridaz-F positron emission tomography (PET). METHODS: In total, 604 patients with suspected CAD underwent flurpiridaz-F PET and Tc-single-photon emission computerized tomography (SPECT) myocardial perfusion imaging (MPI) before invasive coronary angiography (ICA) across 48 sites. MPI images were interpreted by three blinded experts. The primary endpoint was sensitivity and specificity for diagnosing CAD (≥50% stenosis on quantitative coronary angiography), requiring the lower 95% confidence interval to exceed 60% by 2 same blinded expert core lab readers, assessed using one-sided z-test (α = 0.025). Sensitivity and specificity were compared between PET and SPECT and between obese (body mass index [BMI] ≥30 kg/m) and nonobese patients. RESULTS: Of 578 evaluable patients, 298 (51.6%) were obese (mean age: 62.0 years, 64.4% male, mean BMI: 35.6 kg/m) and 117 (39.3%) had CAD by ICA. In obese patients, flurpiridaz-F PET MPI met the primary endpoint, with lower 95% confidence limits greater than 60% and one-sided P < 0.025 by the same 2 readers (Readers 1 and 2). Sensitivity across 3 readers ranged from 70.1% to 88.0% and specificity ranged from 53.6% to 74.0%. In obese patients, flurpiridaz-F PET MPI showed significantly higher sensitivity compared to ᵐTc-SPECT MPI by Readers 1 and 3 (Reader 1: 72.6% vs 60.7%, P = 0.01; Reader 3: 88.0% vs 74.4%, P = 0.002), with non-inferior specificity by the same two readers (Reader 1: 68.0% vs 61.3%; Reader 3: 53.6% vs 50.8%; P < 0.01 for noninferiority, for both), noting that the primary endpoint was met by a partially overlapping reader pair (Readers 1 and 2). Diagnostic performance of flurpiridaz-F PET was higher than SPECT across BMI categories. No statistically significant difference in diagnostic performance was observed between obese and nonobese patients (Sensitivity P = 0.26, specificity P = 0.25 and accuracy P = 1.0). CONCLUSION: Flurpiridaz-F PET MPI demonstrates high diagnostic efficacy for detecting CAD across BMI categories in obese patients compared to ICA and Tc-SPECT, with no loss of diagnostic performance in obese relative to nonobese patients. CLINICAL TRIAL REGISTRATION: NCT03354273.